Novel tetragalnac and peptide containing conjugates and methods for delivery of oligonucleotides

ABSTRACT

Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 16/268,262, filed Feb. 5, 2019, which is acontinuation application of U.S. patent application Ser. No. 15/807,143,filed on Nov. 8, 2017, now U.S. Pat. No. 10,221,205, which is acontinuation application of U.S. patent application Ser. No. 15/481,942,filed on Apr. 7, 2017, now U.S. Pat. No. 9,840,531, which is acontinuation application of U.S. patent application Ser. No. 14/398,369,filed on Oct. 31, 2014, now U.S. Pat. No. 9,655,976, which is anational-stage application of PCT Application No. PCT/US2013/039072,filed on May 1, 2013, which claims the benefit of priority to U.S.Provisional Patent Application Ser. No. 61/641,741, filed May 2, 2012;all of which are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

Scientific efforts focused on the delivery of oligonucleotidessystemically for therapeutic purposes are ongoing. Three highlightedapproaches to oligonucleotide delivery include 1) lipid nanoparticle(LNP) encapsulation, 2) polymer conjugation and 3) single chemicalconjugation. Single chemical conjugation typically employs a targetingligand or a lipid or a solubilizing group or an endosomolytic peptide ora cell penetrating peptide and/or a combination of two or all fourattached to an oligonucleotide. Linkers may be present in the conjugateas well as other functionalities. Single chemical conjugates are knownand attachment of the oligonucleotide occurs either at the 5′- or 3′-endof the oligonucleotide, at both ends, or internally. See WO2005/041859,WO2008/036825, and WO2009/126933.

Considerable amount of literature evidence supports the hypothesis thatthe major hurdles for oligonucleotide delivery are cell uptake andendosomal escape. There remains a need for additional single chemicalconjugates that can provide effective delivery efficiency, cell uptakeand/or endosomal escape.

SUMMARY OF THE INVENTION

Single chemical conjugates comprising tetraGalNAc and peptides disclosedherein have surprising properties of effective delivery efficiency, celluptake and/or endosomal escape.

In one embodiment, a modular composition disclosed herein comprises: 1)a single stranded or double stranded oligonucleotide; 2) one or moretetraGalNAc ligands of Formula (I), (II) or (III) which may be the sameor different:

wherein X is —O—, —S—, —CR¹R²— or —NR¹—, wherein R¹ and R² are eachindependently selected from the group consisting of hydrogen andC₁-C₆alkyl; n is 1, 2, 3, or 4; and the bond with “

” indicates point of attachment; optionally, 3) one or more linkers,which may be the same or

different; 4) one or more peptides independently selected from Table 3,which may be the same or different; and optionally, 5) one or moretargeting ligands, solubilizing agents, pharmacokinetics enhancingagents, lipids, and/or masking agents. In one embodiment, R¹ and R² areeach independently selected from the group consisting of hydrogen,methyl and ethyl. In another embodiment, R¹ and R² are each hydrogen.

In one embodiment, the tetraGalNAc ligand has Formula (II) wherein X,R¹, R² and n are as defined above. In another embodiment, thetetraGalNAc ligand has Formula (III) wherein X, R¹, R² and n are asdefined above:

In another embodiment, a modular composition comprises: 1) a singlestranded or double stranded oligonucleotide; 2) 1-8 tetraGalNAc ligandsof Formula (I), (II) or (III), which may be the same or different,wherein X is —O—, —S—, —CH₂— or —NH—; and n is 1, 2, 3, or 4; 3) 1-24linkers, which may be the same or different; 4) 1-8 peptidesindependently selected from Table 3, which may be the same or different;and optionally, 5) 1-8 targeting ligands, solubilizing agents,pharmacokinetics enhancing agents, lipids, and/or masking agents. thetetraGalNAc ligand has Formula (II) wherein X, R¹, R² and n are asdefined above.

In another embodiment, a modular composition comprises: 1) a singlestranded or double stranded siRNA; 2) 1-8 tetraGalNAc ligands of Formula(I), (II) or (III), which may be the same or different, wherein X is—O—, —S—, —CH₂— or —NH—; and n is 1, 2, 3, or 4; 3) 1-24 linkers, whichmay be the same or different; 4) 1-8 peptides independently selectedfrom Table 3, which may be the same or different; and optionally, 5) 1-8targeting ligands, solubilizing agents, pharmacokinetics enhancingagents, lipids, and/or masking agents.

In another subset of the above embodiments, the linkers are attached tothe oligonucleotide or siRNA at different 2′-positions of the riboserings and/or at different terminal 3′ and/or 5′-positions of theoligonucleotide or siRNA.

In another subset of the above embodiments, the tetraGalNAc ligandsand/or the peptides are attached to the oligonucleotide or siRNAoptionally via linkers.

In another subset of the above embodiments, the tetraGalNAc ligandsand/or the peptides are attached to the oligonucleotide or siRNA atdifferent 2′-positions of the ribose rings and/or at different terminal3′ and/or 5′-positions of the oligonucleotide or siRNA; and thetetraGalNAc ligands and/or the peptides are attached to theoligonucleotide or siRNA optionally via linkers.

In another subset of the above embodiments, X of Formula (I), (II) or(III) is —O—, —S—, or —CH₂—; and n is 1, 2 or 3.

In another subset of the above embodiments, X of Formula (I), (II) or(III) is —O— or —CH₂— and n is 1 or 2.

In another subset of the above embodiments, X of Formula (I), (II) or(III) is —O— and n is 1 or 2.

In another subset of the above embodiments, X of Formula (I), (II) or(III) is —CH₂— and n is 1 or 2.

In another subset of the above embodiments, the composition comprises1-6 tetraGalNAc ligands, or more specifically, 1-4 tetraGalNAc ligands,which may be the same or different.

In another subset of the above embodiments, the composition comprises1-6, peptides, or more specifically, 1-4 peptides, which may be the sameor different.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded; and the tetraGalNAc ligands are attached to theguide strand or the passenger strand of the oligonucleotide or siRNA atdifferent 2′-positions of the ribose rings.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded; and the tetraGalNAc ligands are attached to theguide strand or the passenger strand of the oligonucleotide or siRNA atdifferent terminal 3′ and/or 5′-positions.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded; and the tetraGalNAc ligands are attached to both theguide strand and the passenger strand of the oligonucleotide or siRNA atdifferent 2′-positions of the ribose rings and/or at different terminal3′ and/or 5′-positions.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded; and the peptides are attached to the guide strand orthe passenger strand of the oligonucleotide or siRNA at different2′-positions of the ribose rings of the siRNA.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded; and the peptides are attached to the guide strand orthe passenger strand of the oligonucleotide or siRNA at differentterminal 3′ and/or 5′-positions.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded; and the peptides are attached to both the guidestrand and the passenger strand of the oligonucleotide or siRNA atdifferent 2′-positions of the ribose rings and/or at different terminal3′ and/or 5′-positions.

In another subset of the above embodiments, the tetraGalNAc ligands andthe peptides are attached to the same strand of the oligonucleotide orsiRNA.

In another subset of the above embodiments, the tetraGalNAc ligands andthe peptides are attached to different strands of the oligonucleotide orsiRNA.

In another subset of the above embodiments, the tetraGalNAc ligands andthe peptides are attached to the same or different strands of theoligonucleotide or siRNA via linkers.

In another subset of the above embodiments, each linker is independentlyselected from Table 1.

In another subset of the above embodiments, each linker is independentlyselected from Table 2.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded; and the optional targeting ligands, solubilizingagents, pharmacokinetics enhancing agents, lipids, and/or masking agentsare attached to the same or different strands of the oligonucleotide orsiRNA.

In one embodiment, a modular composition comprises 1) a double strandedsiRNA; 2) 1-8 tetraGalNAc ligands of Formula (IV), (V) or (VI), whichmay be the same or different:

3) 1-24 linkers independently selected from Table 1, which may be thesame or different; 4) 1-8 peptides independently selected from Table 3,which may be the same or different; and, optionally, 5) 1-8 targetingligands, solubilizing agents, pharmacokinetics enhancing agents, lipids,and/or masking agents.

In another embodiment, a modular composition comprises 1) a doublestranded siRNA; 2) 1-4 tetraGalNAc ligands of Formula (IV), (V) or (VI),which may be the same or different; 3) 1-12 linkers independentlyselected from Table 1, which may be the same or different; 4) 1-4peptides independently selected from Table 3, which may be the same ordifferent; and, optionally, 5) 1-4 targeting ligands, solubilizingagents, pharmacokinetics enhancing agents, lipids, and/or maskingagents; wherein the tetraGalNAc ligands and/or the peptides are attachedto the siRNA at different 2′-positions of the ribose rings and/or atdifferent terminal 3′ and/or 5′-positions of the siRNA; and wherein thetetraGalNAc ligands and/or the peptides are attached to the siRNAoptionally via linkers.

In one subset of the above embodiments, the tetraGalNAc ligands and thepeptides are attached to the same strand of the siRNA via linkers.

In another subset of the above embodiments, the tetraGalNAc ligands andthe peptides are attached to different strands of the siRNA via linkers.

In one embodiment, a modular composition comprises 1) a double strandedsiRNA; 2) 1-4 tetraGalNAc ligands of Formula (IV), (V) or (VI), whichmay be the same or different; 3) 1-12 linkers independently selectedfrom Table 2, which may be the same or different; 4) 1-4 peptidesindependently selected from Table 4, which may be the same or different;and, optionally, 5) 1-4 targeting ligands, solubilizing agents,pharmacokinetics enhancing agents, lipids, and/or masking agents;wherein the tetraGalNAc ligands and/or the peptides are attached to thesiRNA at different 2′-positions of the ribose rings and/or at differentterminal 3′ and/or 5′-positions of the siRNA; and wherein thetetraGalNAc ligands and/or the peptides are attached to the siRNA vialinkers.

In one subset of the above embodiment, the tetraGalNAc ligands and thepeptides are attached to the same strand of the siRNA via linkers.

In one subset of the above embodiment, the tetraGalNAc ligands and thepeptides are attached to different strands of the siRNA via linkers.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Non-limiting examples of modular compositions comprising doublestranded oligonucleotides with terminal conjugations.

FIG. 2. Non-limiting examples of modular compositions comprising doublestranded oligonucleotides with terminal conjugations.

FIGS. 3A-3B. Non-limiting examples of modular compositions comprisingdouble stranded oligonucleotides with internal and/or terminalconjugations are shown in FIG. 3A to FIG. 3B.

FIG. 4. Generic structures of each nucleotide [On] or [On,] that containa linker (L-P and/or L-G).

FIGS. 5A-1-5D. Scheme 2 as shown in FIG. 5A-1 to FIG. 5D for preparing BConjugates (Ex. 3-6).

FIGS. 6A-6B. Scheme 3 as shown as FIG. 6A to FIG. 6B for preparingConjugates B6-P32 and B8-seq32 (Ex. 7-8). The figures disclose SEQ IDNO: 32.

FIGS. 7A-7I. Scheme 4 as shown in FIG. 7A, FIG. 7B and FIG. 7C forpreparing B9, B10-seq32 and B11-seq32. The figures disclose SEQ ID NO:32.

Scheme 5 as shown in FIG. 7D-1 and FIG. 7D-2, FIG. 7E and FIG. 7F forpreparing B-13—seq13-b compound. The figures disclose SEQ ID NO: 13.

Scheme 6 as shown in FIG. 7G-1 to FIG. 7G-2 for preparing B16-seq32 andB17-seq32-b compound. FIG. 7H-1, FIG. 7H-2, and FIG. 7I show thepreparation of B15-seq32 and B16-seq32-b. FIGS. 7H-1 to 7I disclose SEQID NO: 32.

FIGS. 8A-8D. Scheme 7 as shown in FIG. 8A to FIG. 8D for preparing C1 toC3, C4-seq32 and C6-seq32 compound. The figures disclose SEQ ID NO: 32.

FIGS. 9A-9E. Scheme 8 as shown in FIG. 9A to FIG. 9E for preparing C7 toC10, C11-seq32 and C12-seq32 compound. The figures disclose SEQ ID NO:32.

FIGS. 10A-10D. Scheme 9 shown in FIG. 10 A to FIG. 10D for preparingC13, C14-seq32 and C15-seq32-a compound. The figures disclose SEQ ID NO:32.

FIGS. 1A-11D. Scheme 10 as shown in FIG. 11A to FIG. 11D for preparingD1, D3 and D4.

FIGS. 12A-1-12B-2. Scheme 11 as shown in FIG. 12A-1 to FIG. 12B-2 forpreparing D5-seq32 and D7-seq32 compound. The figures disclose SEQ IDNO: 32.

FIGS. 13A-13H-2. Scheme 12 as shown in FIG. 13A to FIG. 13H-2 forpreparing E compounds.

FIGS. 14A-1-14B-2. Scheme 13 as shown in FIG. 14A-1 to FIG. 14B-2 forpreparing E8-seq 137 and E10-seq137e compounds. The figures disclose SEQID NO: 137.

FIGS. 15A-15E-2. Scheme 14 as shown in FIG. 15A to FIG. 15E-2 forpreparing F compounds. The figures disclose SEQ ID NO: 463.

FIGS. 16A-1-16B-2. Scheme 15 as shown in FIG. 16A-1 to FIG. 16B-2 forpreparing F6seq 463-f compound. The figures disclose SEQ ID NO: 463.

FIGS. 17A-1-17D-2. Scheme 16 as shown in FIG. 17A-1 to FIG. 17D-2 forpreparing G compounds. The figures disclose SEQ ID NO: 489.

FIGS. 18A-1-18B-2. Scheme 17 as shown in FIG. 18A-I to FIG. 18B-2 forpreparing G compounds. The figures disclose SEQ ID NO: 489.

FIGS. 19A-19I-2. Scheme 19 as shown in FIG. 19A to FIG. 19I-2 forpreparing H10-seq32-h compound. The figures disclose SEQ ID NO: 32.

FIGS. 20A-1-20E-2. Scheme 20 as shown in FIG. 20A-1 to FIG. 20E-2 forpreparing I10-seq1681-f compound. The figures disclose SEQ ID NOS 1737,1737-1739, 1737, 1737, and 1737, respectively, in order of appearance.

FIGS. 21A-21H-2. Scheme 21 as shown in FIG. 21A to FIG. 21H-2 forpreparing J9-seq26-i compound. The figures disclose SEQ ID NO: 26.

FIGS. 22A-1-22D-2. Scheme 22 as shown in FIG. 22A-1 to FIG. 22D-2 forpreparing K6 seq 74-b compound. The figures disclose SEQ ID NO: 74.

FIGS. 23A-23C-2. Scheme 23 as shown in FIG. 23A to FIG. 23C-2 forpreparing L11—seq 463-j compound. The figures disclose SEQ ID NO: 463.

FIGS. 24A-1-24B-2. Scheme 24 as shown in FIG. 24A-1 to FIG. 24B-2 forpreparing M4-seq-j compound. The figures disclose SEQ ID NO: 463.

FIGS. 25A-25B-2. Scheme 25 as shown in FIG. 25A to FIG. 25B-2 forpreparing N4-seq 283-k compound. The figures disclose SEQ ID NO: 283.

FIGS. 26A-1-26B-2. Scheme 26 as shown in FIG. 26A-1 to FIG. 26B-2 forpreparing O3-seq 463-k compound. The figures disclose SEQ ID NO: 463.

FIGS. 27A-1-27B-2. Scheme 27 as shown in FIG. 27A-1 to FIG. 27B-2 forpreparing P2-seq-32-k compound. The figures disclose SEQ ID NO: 13.

FIGS. 28-1-28-2. Scheme 28 as shown in FIG. 28-1 to FIG. 28-2 forpreparing P2-seq 32-m compound. The figures disclose SEQ ID NO: 74.

FIGS. 29A-1-29C-2. Scheme 29 as shown in FIG. 29A-1 to FIG. 29C-2 usedto prepare Q3-seq74-b compound. The figures disclose SEQ ID NO: 74.

FIGS. 30A-30E-3. Scheme 30 as shown in FIG. 30A to FIG. 30E-3 forpreparing R4-seq 27-I compound. The figures disclose SEQ ID NO: 27.

FIGS. 31A-31B. Scheme 32 as shown in FIG. 31A and FIG. 31B for preparingtetraGalNAc-siRNA conjugates.

FIGS. 32A 32B. Scheme 33 as shown in FIG. 32A and FIG. 32B for preparingTetraGalNAc-siRNA Conjugate 19-1.

FIGS. 33A-33B. Scheme 35 as shown in FIG. 33A and FIG. 33B for preparingCompound 26.

FIGS. 34A-34C. Scheme 36 as shown in FIG. 34A to FIG. 34C for preparingCompounds 27 and 28.

FIGS. 35A-35B. Scheme 38 as shown in FIG. 35A and FIG. 35B for preparingConjugates 35-37.

FIGS. 36A-36C. Scheme 39 as shown in FIG. 36A to FIG. 36C for preparingConjugates 38-44.

FIG. 37. Scheme 40 as shown in FIG. 37 showing examples of differentlinkers from Table 2, for conjugating tetraGalNAc to siRNA.

FIGS. 38A-38E. Scheme 41 as shown in FIG. 38A to FIG. 38E for preparingCompounds and/or Conjugates 46-48.

FIGS. 39A-39C. Scheme 42 as shown in FIG. 39A to FIG. 39C for preparingCompounds and/or Conjugates 49-51.

FIG. 40. Scheme 43 as shown in FIG. 40 showing a general description forillustrative purposes of nomenclature used in Table 6.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein are single chemical conjugates comprising a singlestranded or double stranded oligonucleotide; one or more tetraGalNAcligands of Formula (I), (II) or (III), which may be the same ordifferent;

wherein X is —O—, —S—, —CR¹R²— or —NR¹—, wherein R¹ and R² are eachindependently selected from the group consisting of hydrogen andC₁-C₆alkyl; n is 1, 2, 3, or 4; and the bond with “

” indicates the point of attachment; and one or more peptides, which maybe the same or different. Other functionalities, such as targetingligands, solubilizing agents, pharmacokinetics enhancing agents, lipids,and/or masking agents are optionally present. In one embodiment, R¹ andR² are each independently selected from the group consisting ofhydrogen, methyl and ethyl. In another embodiment, R¹ and R² are eachhydrogen.

In one embodiment, the oligonucleotide is a short interfering RNA(siRNA). In another embodiment, the siRNA is a single stranded siRNA. Inanother embodiment, the siRNA is a double stranded siRNA.

The use of the tetraGalNAc disclosed herein provides effective deliveryof the oligonucleotide or siRNA by directing the modular composition toa particular cell. For example, the targeting ligand may specifically ornon-specifically bind with a molecule on the surface of a target celland facilitate internalization of the ligand-siRNA conjugate.

The peptides may function as endosomolytic, cell penetrating and/orfusogenic agents. In addition, the peptide may have cationic,zwitterionic, neutral, anionic character. Incorporation of both thetetraGalNAc and the peptide in the modular composition may furtherimprove the delivery efficiency of the oligonucleotide or siRNA.

A linker may be present between each peptide and the oligonucleotide orbetween each tetraGalNAc and the oligonucleotide. The linkers areattached to the oligonucleotide at different 2′-positions of the riboserings and/or the terminal 3′ and/or 5′-positions of the oligonucleotide.

In one embodiment, a modular composition comprises 1) a single strandedor double stranded oligonucleotide; 2) one or more tetraGalNAc ligandsof Formula (I), (II) or (III), which may be the same or different,wherein X is —O—, —S—, —CH₂— or —NH—; n is 1, 2, 3, or 4; and the bondwith “

” indicates the point of attachment; optionally, 3) one or more linkers,which may be the same or different; 4) one or more peptidesindependently selected from Table 3, which may be the same or different;and optionally, 5) one or more targeting ligands, solubilizing agents,pharmacokinetics enhancing agents, lipids, and/or masking agents.

In another embodiment, a modular composition comprises 1) a singlestranded or double stranded oligonucleotide; 2) 1-8 tetraGalNAc ligandsof Formula (I), (II) or (III), which may be the same or different,wherein X is —O—, —S—, —CH₂— or —NH—; n is 1, 2, 3, or 4; 3) 1-24linkers, which may be the same or different; 4) 1-8 peptidesindependently selected from Table 3, which may be the same or different;and optionally, 5) 1-8 targeting ligands, solubilizing agents,pharmacokinetics enhancing agents, lipids, and/or masking agents.

In another embodiment, a modular composition comprises 1) a singlestranded or double stranded siRNA; 2) 1-8 tetraGalNAc ligands of Formula(I), (II) or (III), which may be the same or different, wherein X is—O—, —S—, —CH₂— or —NH—; n is 1, 2, 3, or 4; 3) 1-24 linkers, which maybe the same or different; 4) 1-8 peptides independently selected fromTable 3, which may be the same or different; and optionally, 5) 1-8targeting ligands, solubilizing agents, pharmacokinetics enhancingagents, lipids, and/or masking agents.

In one subset of the above embodiments, the tetraGalNAc ligands and/orthe peptides are attached to the oligonucleotide or siRNA at different2′-positions of the ribose rings and/or at different terminal 3′ and/or5′-positions of the oligonucleotide or siRNA.

In another subset of the above embodiments, the tetraGalNAc ligandsand/or the peptides are attached to the oligonucleotide or siRNAoptionally via linkers. In one embodiment, the linkers are present.

In another subset of the above embodiments, the tetraGalNAc ligandsand/or the peptides are attached to the oligonucleotide or siRNA atdifferent 2′-positions of the ribose rings and/or at different terminal3′ and/or 5′-positions of the oligonucleotide or siRNA; and thetetraGalNAc ligands and/or the peptides are attached to theoligonucleotide or siRNA via linkers.

In another subset of the above embodiments, the tetraGalNAc ligands areattached to the oligonucleotide or siRNA via linkers and the linkers areattached to the oligonucleotide or siRNA at different 2′-positions ofthe ribose rings.

In another subset of the above embodiments, the tetraGalNAc ligands areattached to the oligonucleotide or siRNA via linkers and the linkers areattached to the oligonucleotide or siRNA at different terminal 3′ and/or5′-positions of the oligonucleotide.

In another subset of the above embodiments, X is —O—, —S—, or —CH₂—. Inanother embodiment, X is —O— or —CH₂—. In another embodiment, n is 1, 2or 3. In another embodiment, X is —O— and n is 1 or 2. In anotherembodiment, X is —CH₂— and n is 1 or 2. In another embodiment, X is —O—and n is 1. In yet another embodiment, X is —CH₂— and n is 1.

In another subset of the above embodiments, the oligonucleotide or siRNAis single stranded. In another embodiment, the oligonucleotide or siRNAis double stranded.

In another subset of the above embodiments, the composition comprises1-6 tetraGalNAc ligands. In another embodiment, the compositioncomprises 1-4 tetraGalNAc ligands. In another embodiment, thecomposition comprises 1-2 tetraGalNAc ligands. In yet anotherembodiment, the composition comprises 1 tetraGalNAc ligand.

In another subset of the above embodiments, the composition comprises1-6 peptides. In another embodiment, the composition comprises 1-4peptides. In another embodiment, the composition comprises 1-2 peptides.In yet another embodiment, the composition comprises 1 peptide.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the tetraGalNAc ligands are attached to the guidestrand at different 2′-positions of the ribose rings.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded the tetraGalNAc ligands are attached to the guidestrand at different terminal 3′ and/or 5′-positions.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the tetraGalNAc ligands are attached to thepassenger strand at different 2′-positions of the ribose rings.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the tetraGalNAc ligands are attached to thepassenger strand at different terminal 3′ and/or 5′-positions.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the tetraGalNAc ligands are attached to both theguide strand and the passenger strand at different 2′-positions of theribose rings and/or different terminal 3′ and/or 5′-positions.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the peptides are attached to the guide strand atdifferent 2′-positions of the ribose rings.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the peptides are attached to the guide strand atdifferent terminal 3′ and/or 5′-positions.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the peptides are attached to the passenger strandat different 2′-positions of the ribose rings.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the peptides are attached to the passenger strandat different terminal 3′ and/or 5′-positions.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the peptides are attached to both the guidestrand and the passenger strand at different 2′-positions of the riboserings and/or different terminal 3′ and/or 5′-positions.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the tetraGalNAc ligands and the peptides areattached to the same or different strands via linkers. In oneembodiment, each linker is independently selected Table 1. In anotherembodiment, each linker is independently selected Table 2.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the tetraGalNAc ligands and the peptides areattached to the same strand.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the tetraGalNAc ligands and the peptides areattached to different strands.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the optional targeting ligands, solubilizingagents, pharmacokinetics enhancing agents, lipids, and/or masking agentsare attached to the same or different strands.

In another subset of the above embodiments, the oligonucleotide or siRNAis double stranded and the optional targeting ligands, solubilizingagents, pharmacokinetics enhancing agents, lipids, and/or masking agentsare attached to the same or different strands via linkers. In oneembodiment, each linker is independently selected from Table 1. Inanother embodiment, each linker is independently selected from Table 2.

In one embodiment, a modular composition comprises 1) a single strandedor double stranded siRNA; 2) 1-8 tetraGalNAc ligands of Formula (I),(II) or (III), which may be the same or different; wherein X is —O—,—S—, —CH₂— or —NH—; and n is 1, 2, 3, or 4; 3) 1-24 linkers, which maybe the same or different; 4) 1-8 peptides independently selected fromTable 3, which may be the same or different; and optionally, 5) 1-8targeting ligands, solubilizing agents, pharmacokinetics enhancingagents, lipids, and/or masking agents; wherein the tetraGalNAc ligandsand/or the peptides are attached to the siRNA at different 2′-positionsof the ribose rings and/or at different terminal 3′ and/or 5′-positionsof the siRNA; and wherein the tetraGalNAc ligands and/or the peptidesare attached to the siRNA optionally via linkers. In one embodiment, thelinkers are present. In another embodiment, X is —O—, —S—, or —CH₂—, andn is 1, 2 or 3. In another embodiment, X is —O— or —CH₂—, and n is 1 or2.

In another embodiment, a modular composition comprises 1) a doublestranded siRNA; 2) 1-6 tetraGalNAc ligands of Formula (I), (II) or(III), which may be the same or different; wherein X is —O—, —S—, or—CH₂—; and n is 1, 2 or 3; 3) 1-18 linkers, which may be the same ordifferent; 4) 1-6 peptides independently selected from Table 3, whichmay be the same or different; and optionally, 5) 1-6 targeting ligands,solubilizing agents, pharmacokinetics enhancing agents, lipids, and/ormasking agents; wherein the tetraGalNAc ligands and/or the peptides areattached to the siRNA at different 2′-positions of the ribose ringsand/or at different terminal 3′ and/or 5′-positions of the siRNA; andwherein the tetraGalNAc ligands and/or the peptides are attached to thesiRNA optionally via linkers. In one embodiment, the linkers arepresent. In another embodiment, X is —O—, —S—, or —CH₂— and n is 1 or 2.In another embodiment, the linkers are independently selected fromTable 1. In another embodiment, the linkers are independently selectedfrom Table 2. In another embodiment, the peptides of 4) areindependently selected from Table 4.

In another embodiment, a modular composition comprises 1) a doublestranded siRNA; 2) 1-4 tetraGalNAc ligands of Formula (I), (II) or(III), which may be the same or different; wherein X is —O—, —S—, or—CH₂—; and n is 1 or 2; 3) 1-12 linkers, which may be the same ordifferent; 4) 1-4 peptides independently selected from Table 3, whichmay be the same or different; and optionally, 5) 1-4 targeting ligands,solubilizing agents, pharmacokinetics enhancing agents, lipids, and/ormasking agents; wherein the tetraGalNAc ligands and/or the peptides areattached to the siRNA at different 2′-positions of the ribose ringsand/or at different terminal 3′ and/or 5′-positions of the siRNA; andwherein the tetraGalNAc ligands and/or the peptides are attached to thesiRNA via linkers. In one embodiment, X is —O— or —CH₂— and n is 1 or 2.In another embodiment, the linkers are independently selected fromTable 1. In another embodiment, the linkers are independently selectedfrom Table 2. In another embodiment, the peptides are independentlyselected from Table 4.

In another embodiment, a modular composition comprises 1) a doublestranded siRNA; 2) 1-4 tetraGalNAc ligands of Formula (IV), (V) or (VI),which may be the same or different:

3) 1-12 linkers independently selected from Table 1, which may be thesame or different; 4) 1-4 peptides independently selected from Table 3,which may be the same or different; and optionally, 5) 1-4 targetingligands, solubilizing agents, pharmacokinetics enhancing agents, lipids,and/or masking agents; wherein the tetraGalNAc ligands and/or thepeptides are attached to the siRNA at different 2′-positions of theribose rings and/or at different terminal 3′ and/or 5′-positions of thesiRNA; and wherein the tetraGalNAc ligands and/or the peptides areattached to the siRNA via linkers.

In another embodiment, a modular composition comprises 1) a doublestranded siRNA; 2) 1-4 tetraGalNAc ligands of Formula (IV), (V) or (VI);3) 1-12 linkers independently selected from Table 2, which may be thesame or different; 4) 1-4 peptides independently selected from Table 4,which may be the same or different; and optionally, 5) 1-4 targetingligands, solubilizing agents, pharmacokinetics enhancing agents, lipids,and/or masking agents; wherein the tetraGalNAc ligands and/or thepeptides are attached to the siRNA at different 2′-positions of theribose rings and/or at different terminal 3′ and/or 5′-positions of thesiRNA; and wherein the tetraGalNAc ligands and/or the peptides areattached to the siRNA via linkers.

In one subset of the above embodiments, the tetraGalNAc ligands and/orthe peptides are attached to the siRNA via linkers; and wherein thetetraGalNAc ligands and/or the peptides are attached to the same strand.

In another subset of the above embodiments, the tetraGalNAc ligandsand/or the peptides are attached to the siRNA via linkers; and whereinthe tetraGalNAc ligands and the peptides are attached to differentstrands.

To illustrate the invention via cartoon, the invention features amodular composition, comprising an oligonucleotide ([O₁][O₂][O₃] . . .[O_(n)]), one or more tetraGalNAc(s) ligands (G), one or more linker(s)(L), one or more peptide(s) (P), and one or more optional lipid(s) (X),one or more targeting ligand(s) (X), and/or one or more solubilizinggroup(s) (X).

In an embodiment, the modular composition may have the formula:

G-L-[O₁][O₂][O₃] . . . [O_(n)]-L-P.

In another embodiment, the modular composition may have the formula:

P-L-[O₁][O₂][O₃] . . . [O_(n)]-L-G.

Non-limiting examples of modular compositions comprising double strandedoligonucleotides with terminal conjugations are shown in FIG. 1.

Non-limiting examples of modular compositions comprising double strandedoligonucleotides with terminal conjugations are shown in FIG. 2.

Non-limiting examples of modular compositions comprising double strandedoligonucleotides with internal and/or terminal conjugations are shown inFIG. 3A and FIG. 3B.

These examples are used as illustration only. One skilled in the artwill recognize that a variety of permutations for placing the desiredcomponents on the passenger and guide strand exist.

Any number of linkers, and therefore any number of peptides, can beattached to the oligonucleotide. The range of numbers of linkers is from1-16. A more preferred range of numbers of linkers is from 1-12, or morespecifically, 1-8, or even more specifically, 1-4.

The range of numbers of tetraGalNAc ligands is from 1-8. A morepreferred range of numbers of tetraGalNAc ligands is from 1-6, or morespecifically, 1-4, or even more specifically, 1-2.

The range of numbers of peptides is from 1-8. A more preferred range ofnumbers of peptides is from 1-6, or more specifically, 1-4, or even morespecifically, 1-2.

The two strands contain n and n′ nucleotides respectively. The numbers nand n′ can be equal or different. The numbers are integers ranging from8 to 50. Preferably, the numbers are integers ranging from 12-28. Morepreferably, the numbers are integers ranging from 19-21.

As an example, each nucleotide [O_(n)] or [O_(n′)], that contains alinker (L-P and/or L-G) has generic structures as shown in FIG. 4.

For each nucleotide, 1) E=oxygen (O) or sulfur (S); 2) Base=A, U, G orC, which can be modified or unmodified; 3) D is the connection pointbetween ribose ring and linker L, D=oxygen (O), sulfur (S, S(O) orS(O)₂), nitrogen (N—R, wherein R═H, alkyl, L-P or L-X), carbon (CH—R,wherein R═H, alkyl, L-P, or L-X), or phosphorus (P(O)R or P(O)(OR),wherein R=alkyl, L-P, or L-X). Preferably, D=oxygen (O).

The two nucleotides [O_(n-1)] and [O_(n)] or [O_(n′-1)] and [O_(n′)] areconnected via phosphodiester or thio-phosphodiester bonds.

When the oligonucleotide is a double-stranded oligonucleotide, the“G-L”, “P-L” and the lipid, targeting ligand, and/or solubilizing groupmay be located on the same strand or on different strands.

In some embodiments, the “G-L” and “P-L” are on the same strand.

In some embodiments, the “G-L” and “P-L” are on the passenger strand.

In some embodiments, the “G-L” and “P-L” are on the guide strand.

In some embodiments, the “G-L” and “P-L” are located on differentstrands.

In some embodiments, the “G-L” is on the passenger strand while the“P-L” is on the guide strand.

In some embodiments, the “G-L” and “P-L” are on different strands but onthe same terminal end of the double-stranded oligonucleotide.

In some embodiments, the “G-L” and “P-L” are on different strands and onthe opposite terminal ends of the double-stranded oligonucleotide.

In some embodiments, the “G-L” can be located on multiple terminal endsof either the passenger or guide strand and “P-L” can be located on theremaining terminal ends of the passenger and guide strands.

In some embodiments, one “G-L” and two or more “P-L” are present in theoligonucleotide.

In some embodiments, two or more “G-L” and two or more “P-L” are presentin the oligonucleotide.

In some embodiments, when the oligonucleotide is a double-strandedoligonucleotide and multiple “G-L” and/or “P-L” are present, suchmultiple “G-L” components and/or “P-L” may all be present in one strandor both strands of the double stranded oligonucleotide.

When multiple “G-L” components and/or “P-L” are present, they may all bethe same or different.

In some embodiments, the “G-L” and/or “P-L” are on internal nucleotidesonly (i.e. excluding the 3′- and 5′-terminal ends of theoligonucleotide).

In another aspect, the invention includes a method of delivering anoligonucleotide or siRNA to a cell. The method includes (a) providing orobtaining a modular composition disclosed herein; (b) contacting a cellwith the modular composition; and (c) allowing the cell to internalizethe modular composition.

The method can be performed in vitro, ex vivo or in vivo, e.g., to treata subject identified as being in need of an oligonucleotide or siRNA. Asubject in need of said oligonucleotide is a subject, e.g., a human, inneed of having the expression of a gene or genes, e.g., a gene relatedto a disorder, downregulated or silenced.

In one aspect, the invention provides a method for inhibiting theexpression of one or more genes. The method comprising contacting one ormore cells with an effective amount of an oligonucleotide of theinvention, wherein the effective amount is an amount that suppresses theexpression of the one or more genes. The method can be performed invitro, ex vivo or in vivo.

The methods and compositions of the invention, e.g., the modularcomposition described herein, can be used with any oligonucleotides orsiRNAs known in the art. In addition, the methods and compositions ofthe invention can be used for the treatment of any disease or disorderknown in the art, and for the treatment of any subject, e.g., anyanimal, any mammal, such as any human. One of ordinary skill in the artwill also recognize that the methods and compositions of the inventionmay be used for the treatment of any disease that would benefit fromdownregulating or silencing a gene or genes.

The methods and compositions of the invention, e.g., the modularcomposition described herein, may be used with any dosage and/orformulation described herein, or any dosage or formulation known in theart. In addition to the routes of administration described herein, aperson skilled in the art will also appreciate that other routes ofadministration may be used to administer the modular composition of theinvention.

Oligonucleotide

An “oligonucleotide” as used herein, is a double stranded or singlestranded, unmodified or modified RNA or DNA. Examples of modified RNAsinclude those which have greater resistance to nuclease degradation thando unmodified RNAs. Further examples include those which have a 2′ sugarmodification, a base modification, a modification in a single strandoverhang, for example a 3′ single strand overhang, or, particularly ifsingle stranded, a 5′ modification which includes one or more phosphategroups or one or more analogs of a phosphate group. Examples and afurther description of oligonucleotides can be found in WO2009/126933,which is hereby incorporated by reference.

In an embodiment, an oligonucleotide is an antisense, miRNA, peptidenucleic acid (PNA), poly-morpholino (PMO) or siRNA. The preferredoligonucleotide is an siRNA. Another preferred oligonucleotide is thepassenger strand of an siRNA. Another preferred oligonucleotide is theguide strand of an siRNA.

siRNA

siRNA directs the sequence-specific silencing of mRNA through a processknown as RNA interference (RNAi). The process occurs in a wide varietyof organisms, including mammals and other vertebrates. Methods forpreparing and administering siRNA and their use for specificallyinactivating gene function are known. siRNA includes modified andunmodified siRNA. Examples and a further description of siRNA can befound in WO2009/126933, which is hereby incorporated by reference.

A number of exemplary routes of delivery are known that can be used toadminister siRNA to a subject. In addition, the siRNA can be formulatedaccording to any exemplary method known in the art. Examples and afurther description of siRNA formulation and administration can be foundin WO2009/126933, which is hereby incorporated by reference.

The phrases “short interfering nucleic acid”, “siNA”, “short interferingRNA”, “siRNA”, “short interfering nucleic acid molecule”,“oligonucleotide”, “short interfering oligonucleotide molecule”, or“chemically modified short interfering nucleic acid molecule” refer toany nucleic acid molecule capable of inhibiting or down regulating geneexpression or viral replication by mediating RNA interference (“RNAi”)or gene silencing in a sequence-specific manner. These terms can referto both individual nucleic acid molecules, a plurality of such nucleicacid molecules, or pools of such nucleic acid molecules. The siNA can bea double-stranded nucleic acid molecule comprising self-complementarysense and antisense strands, wherein the antisense strand comprises anucleotide sequence that is complementary to a nucleotide sequence in atarget nucleic acid molecule or a portion thereof and the sense strandcomprises a nucleotide sequence corresponding to the target nucleic acidsequence or a portion thereof. The siNA can be a polynucleotide with aduplex, asymmetric duplex, hairpin or asymmetric hairpin secondarystructure, having self-complementary sense and antisense regions,wherein the antisense region comprises a nucleotide sequence that iscomplementary to a nucleotide sequence in a separate target nucleic acidmolecule or a portion thereof and the sense region comprises anucleotide sequence corresponding to the target nucleic acid sequence ora portion thereof. The siNA can be a circular single-strandedpolynucleotide having two or more loop structures and a stem comprisingself-complementary sense and antisense regions, wherein the antisenseregion comprises nucleotide sequence that is complementary to anucleotide sequence in a target nucleic acid molecule or a portionthereof and the sense region comprises a nucleotide sequencecorresponding to the target nucleic acid sequence or a portion thereof,and wherein the circular polynucleotide can be processed either in vivoor in vitro to generate an active siNA molecule capable of mediatingRNAi. The siNA can also comprise a single-stranded polynucleotide havinga nucleotide sequence complementary to nucleotide sequence in a targetnucleic acid molecule or a portion thereof (for example, where such siNAmolecule does not require the presence within the siNA molecule of anucleotide sequence corresponding to the target nucleic acid sequence ora portion thereof), wherein the single-stranded polynucleotide canfurther comprise a terminal phosphate group, such as a 5′-phosphate (seefor example, Martinez et al., 2002, Cell, 110, 563-574 and Schwarz etal., 2002, Molecular Cell, 10, 537-568), or 5′,3′-diphosphate.

siRNA directs the sequence-specific silencing of mRNA through a processknown as RNA interference (RNAi). The process occurs in a wide varietyof organisms, including mammals and other vertebrates. Methods forpreparing and administering siRNA and their use for specificallyinactivating gene function are known. As used herein, siRNA includeschemically modified and unmodified nucleic acid molecules capable ofinhibiting or down regulating gene expressions. Examples and a furtherdescription of siRNA can be found in WO2009/126933, which is herebyincorporated by reference.

A number of exemplary routes of delivery are known that can be used toadminister siRNA to a subject. In addition, the siRNA can be formulatedaccording to any exemplary method known in the art. Examples and afurther description of siRNA formulation and administration can be foundin WO2009/126933, which is hereby incorporated by reference.

Linkers

The covalent linkages between the tetraGalNAc and the oligonucleotide orsiRNA of the modular composition and/or between the peptide and theoligonucleotide or siRNA may be mediated by a linker. This linker may becleavable or non-cleavable, depending on the application. In certainembodiments, a cleavable linker may be used to release theoligonucleotide after transport from the endosome to the cytoplasm. Theintended nature of the conjugation or coupling interaction, or thedesired biological effect, will determine the choice of linker group.Linker groups may be combined or branched to provide more complexarchitectures. Suitable linkers include those as described inWO2009/126933, which is hereby incorporated by reference.

In one embodiment, the linkers of the instant invention are shown inTable 1:

TABLE 1

R = H, Boc, Cbz, Ac, PEG, lipid, targeting ligand, linker(s) and/orpeptide(s). n = 0 to 750. ″nucleotide″ can be substituted withnon-nucleotide moiety such as abasic or linkers as are generally knownin the art. enzymatically cleavable linker = linker cleaved by enzyme;e.g., protease or glycosidase

In another embodiment, the preferred linkers are shown in Table 2.

TABLE 2

R = H, Boc, Cbz, Ac, PEG, lipid, targeting ligand, linker(s) and/orpeptide(s). n = 0 to 750. ″nucleotide″ can be substituted withnon-nucleotide moiety such as abasic or linkers as are generally knownin the art. enzymatically cleavable linker = linker cleaved by enzyme;e.g., protease or glycosidase

Commercial linkers are available from various suppliers such as Pierceor Quanta Biodesign including combinations of said linkers. In addition,commercial linkers attached via phosphate bonds can be usedindependently as linkers or in combination with said linkers. Thelinkers may also be combined to produce more complex branchedarchitectures accommodating from 1 to 8 peptides as illustrated in onesuch example below:

Peptides

For macromolecular drugs and hydrophilic drug molecules, which cannoteasily cross bilayer membranes, entrapment in endosomal/lysosomalcompartments of the cell is thought to be the biggest hurdle foreffective delivery to their site of action. Without wishing to be boundby theory, it is believed that the use of peptides will facilitateoligonucleotide escape from these endosomal/lysosomal compartments oroligonucleotide translocation across a cellular membrane and releaseinto the cytosolic compartment. In certain embodiments, the peptides ofthe present invention may be polycationic or amphiphilic or polyanionicor zwitterionic or lipophilic or neutral peptides or peptidomimeticswhich can show pH-dependent membrane activity and/or fusogenicity. Apeptidomimetic may be a small protein-like chain designed to mimic apeptide.

In some embodiments, the peptide is a cell-permeation agent, preferablya helical cell-permeation agent. These peptides are commonly referred toas Cell Penetrating Peptides. See, for example, “Handbook of CellPenetrating Peptides” Ed. Langel, U.; 2007, CRC Press, Boca Raton, Fla.Preferably, the component is amphipathic. The helical agent ispreferably an alpha-helical agent, which preferably has a lipophilic anda lipophobic phase. A cell-permeation agent can be, for example, a cellpermeation peptide, cationic peptide, amphipathic peptide or hydrophobicpeptide, e.g. consisting primarily of Tyr, Trp and Phe, dendrimerpeptide, constrained peptide or crosslinked peptide. Examples of cellpenetrating peptides include Tat, Penetratin, and MPG. For the presentinvention, it is believed that the cell penetrating peptides can be a“delivery” peptide, which can carry large polar molecules includingpeptides, oligonucleotides, and proteins across cell membranes. Cellpermeation peptides can be linear or cyclic, and include D-amino acids,“retro-inverso” sequences, nonpeptide or pseudo-peptide linkages,peptidyl mimics. In addition the peptide and peptide mimics can bemodified, e.g. glycosylated, pegylated, or methylated. Examples and afurther description of peptides can be found in WO2009/126933, which ishereby incorporated by reference. Synthesis of peptides is well known inthe art.

The peptides may be conjugated at either end or both ends by addition ofa cysteine or other thiol containing moiety to the C- or N-terminus.When not functionalized on the N-terminus, peptides may be capped by anacetyl group, or may be capped with a lipid, a PEG, or a targetingmoiety. When the C-terminus of the peptides is unconjugated orunfunctionalized, it may be capped as an amide, or may be capped with alipid, a PEG, or a targeting moiety.

Suitable peptides that can be used in the conjugates disclosed hereinare listed in Table 3 below:

TABLE 3 Peptide Sequence Listing and ID Sequence SEQ IDCGLFEAIEEFIENLWELLIDGWYGYGRKKRRQRR SEQ ID NO: 1CGLFEAIEGFIENGWEGMIDGWYGYGHKKHHQHH SEQ ID NO: 2C-bAla-LFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 3CGLFEAIEGFIENGLKGLIDWWYGYGRKKRRQRR SEQ ID NO: 4CGLFEAIEGFIEWGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 5CRRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLG SEQ ID NO: 6CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQR SEQ ID NO: 7CYGRKKRRQRRGLFEAIEGFIENGWEGMIDGWYG SEQ ID NO: 8 CIFGAIAGFIKNILKGLIDGSEQ ID NO: 9 CIFGAIAGFIRNIW SEQ ID NO: 10CGLFHALLHLLHSLWHGLLHAWYGYGHKKHHQHR SEQ ID NO: 11CGLFEAIEGLIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 12CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 13CGLFEAIEGFIENGWEGLIDGWYGYGOOOOOQRR (O = ornithine) SEQ ID NO: 14CGLFGAIEGFIENGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 15CGLFEAIEGFLENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 16CGLFEAIEGFIENGLEGMIDGWYGYGRKKRRQRR SEQ ID NO: 17CGLFGAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 18CGLFEAIEGFIENGWEG-Nle-IDGWYGYGRKKRRQRR SEQ ID NO: 19CGIFGAIAGFIKNIWKGLIDW SEQ ID NO: 20 CYGRKKRRQRRGLFEAIEGFIENGWKGLIDAWYGSEQ ID NO: 21 CGLLEALEGLLESLWEGLLEAWYGYGRKKRRQRR SEQ ID NO: 22CGLFEAIEGFIENGWEGMIDNWYGYGRKKRRQRR SEQ ID NO: 23CIFGAIAGFIKNIWEGLIEAWYGLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 24CIFGAIAGFIKNIWEGLIDAF SEQ ID NO: 25 CIFGAIAGFIKNIWEGLI SEQ ID NO: 26CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 27CGLFEAIAGFIEGGWPGLINGWYGYGRKKRRQRRLHLLHHLLHHLHHLLHHLLHLL SEQ ID NO: 28HHLLHHL CGLFEAIEGFIENGWEGMIDGWYGGGGLHLLHHLLHHLHHLLHHLLHLLHHLLHHLSEQ ID NO: 29 CGLFEAIEGFIENGWEGMIDGWYGLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 30 CGLFEALLELLESLWELLLEAYGRKKRRQRR SEQ ID NO: 31CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 32CGLFEAIEGFIENGWEGMADGWYGYGRKKRRQRR SEQ ID NO: 33CGIFGAIAGFIKNIWEGLIDWWYGYGRKKRRQRR SEQ ID NO: 34CGFLPAIAGILSQLFEGLIDGWYGYGRKKRRQRR SEQ ID NO: 35 CFFGAIWGFIKSILSEQ ID NO: 36 CIFGAIAGFIKNIWKGLIDWWYG SEQ ID NO: 37CGLFEAIEGFIWNGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 38CGLFEAIAEFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 39CYGRKKRRQRRGLFEAIEGFIENGWKGLIDWWYG SEQ ID NO: 40CGLFEAIEGFIEEGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 41CGLFEAIEGFIENAWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 42CGLFEAIEGFIENGWEGMIDLWYGYGRKKRRQRR SEQ ID NO: 43 CRLLRLLLRLWRRLLRLLRSEQ ID NO: 44 CGGFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 45CGLFEKIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 46CGLFEAIEGFIENGWENMIDGWYGYGRKKRRQRR SEQ ID NO: 47 CIFGAIAGFIKNILKGLSEQ ID NO: 48 CIFGAIAGFIKNILKGLIDGWYG SEQ ID NO: 49CGLFEAIEGFIENGWEGMIDGWYG-(PEG)3-YGRKKRRQRR SEQ ID NO: 50CGLFEALLELLESLWELLLEAYGRKKRRQRRLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 51CYGRKKRRQRRWEAALAEALAEALAEHLAEALAEALEALAA SEQ ID NO: 52CIFGAIAGFIKNIWEGLIDGWYGKLALKLALKALKAALKLA SEQ ID NO: 53CFFGAIWEFIRSILEGLIDGWYGYGRKKRRQRR SEQ ID NO: 54CGLFHALLHLLHSLWHLLLHAWYGYGRKKRRQRR SEQ ID NO: 55CGLFHALLHLLHSLWHLLLHAWYGYGHKKHHQHR SEQ ID NO: 56CGLFGALLELLESLWKGLLEWYGRKKRRQRR SEQ ID NO: 57CRRQRRKKRGYGYWGDILGEWGNEIFGEIAEFLG SEQ ID NO: 58CGLFEALEGFLENGWEGLLDGWYGYGROORRQRR (O = ornithine) SEQ ID NO: 59CGLFGEIEELIENGLKNLIDWWYGYGRKKRRQRR SEQ ID NO: 60CRRQRRKKRGYGYWWDILGKWGNEIFGEIAEFLG all (D) aminos SEQ ID NO: 61CGIFGAIAGFIKNIL SEQ ID NO: 62 CGIFGAIAGLLKNIFK SEQ ID NO: 63CIFGAIAGFIKNIWKGLIDW SEQ ID NO: 64 CIFGAIAGFIKNIWK SEQ ID NO: 65CGLFEEIEGFIENGWEGLIDWWYGYGHKKHHQHR SEQ ID NO: 66CGLFGEIEELIENGLKNLIDWWYGYGHKKHHQHR SEQ ID NO: 67CGLFEEIEEFIENGWEGLIDWWYGYGHKKHHQHR SEQ ID NO: 68stearyl-WEAALAEALAEALAEHLAEALAEALEALAAYGRKKRRQRRC SEQ ID NO: 69CGLFEAIEGFIENGWKGLIDGWYGGLFEAIEGFIENGWKGLIDWWYG SEQ ID NO: 70CGFFHAFFHFFHSFWHGFFEA SEQ ID NO: 71 CGNFGEIEELIEEGLENLIDWWNGSEQ ID NO: 72 CFFGAIWEFIRNILEGF SEQ ID NO: 73 CFFGAIWEFIHSILSEQ ID NO: 74 CGLFHALLHLLHSLWHGLLEA SEQ ID NO: 75 CIFGAIAGFIKNIWEGLSEQ ID NO: 76 CIFGAIAGLLKNIFEGLIDGWYGYGRKKRRQRR SEQ ID NO: 77CGFIGAIANLLSKIFEGLIDGWYGYGRKKRRQRR SEQ ID NO: 78CGLFEAIEELIENLWKGLIDAWYGYGRKKRRQRR SEQ ID NO: 79 CGIFGAIAGLLKNIFKGLIDASEQ ID NO: 80 CGIFGAIAGLLKNIFKGLIDW SEQ ID NO: 81 CGIFEAIAGLLKNIFKSEQ ID NO: 82 CGIFEEIAGLLKNIFK SEQ ID NO: 83CGLFEAIAGFIEGGWPGLINGWYGYGRKKRRQRRLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 84CGLFEAIEGFIENGWKGMIDWWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 85CGLFGEIEEFIENGWKGLIDWWYG SEQ ID NO: 86CIFGAIAGFIKNIWLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 87CGIFGAIEGFIENGWKGLIDAWYGYRKKRRQRR SEQ ID NO: 88CELFGAIEGFIENGWKGLIDVWWYGYGRKKRRQRR SEQ ID NO: 89CIFGIDDLIIGLLFVAIVEAGIGGYLLGSYGRKKRRQRR SEQ ID NO: 90GLFGALAEALAEALAEHLAEALAEALEALAAGGSC SEQ ID NO: 91CGFIGAIANLLSKIFEGLIDGWYGYGRKKRRQRR all (D) SEQ ID NO: 92CFFGAIWEFIRSILKGLI SEQ ID NO: 93 CFFGAIWEFIRSILK SEQ ID NO: 94CFFGAIWEFIRSILE SEQ ID NO: 95 CIFGAIAGFIKNIWE SEQ ID NO: 96CIFGAIAGFIKNIWKGLIDA SEQ ID NO: 97 CFFEAIEEFIKNILK SEQ ID NO: 98CIFGAIAGLLRNIF SEQ ID NO: 99 CGIFGAIAGLLKNIW SEQ ID NO: 100CLFGAIWEFIKSIL SEQ ID NO: 101 CFWGAIWEFIKSIL SEQ ID NO: 102CFGGAIWEFIKSIL SEQ ID NO: 103 CFAGAIWEFIKSIL SEQ ID NO: 104CGLFEAIEGFIENGWEGM(SO2)IDGWYGYGRKKRRQRR SEQ ID NO: 105CGLFEAIEGFIENGWEGMIDWWYGYGRKKRRQRR SEQ ID NO: 106 CFFGAIWEFIKSIGSEQ ID NO: 107 CFFGAIWEFIKSIA SEQ ID NO: 108 CFFGAIWEFIKSINSEQ ID NO: 109 CFFGAIWEFIKSIW SEQ ID NO: 110CFFGAIWEFIKSILEGLIDWWYGYGHKKHHQHR SEQ ID NO: 111Ac-CLHLLHHLLHHLHHLLHHLLHLLHHLLHHL-NH2 SEQ ID NO: 112Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLGGGRKKRRQRRRPPQC-NH2 SEQ ID NO: 113CRKKRRQRRRPPQGGGLHLLHHLLHHLHHLLHHLLHLLHHLLHHL SEQ ID NO: 114CLHLLHHLLHHLHHLLHHLLHLLHHLLHHLGGGRKKRRQRRRPPQ SEQ ID NO: 115CGLFHAIAHFIHGGWHGLIHGWYGYGRKKRRQRR SEQ ID NO: 116CGLFKAIAKFIKGGWKGLIKGWYGYGRKKRRQRR SEQ ID NO: 117CGLFEAIAGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 118CWEAALAEALAEALAEHLAEALAEALEALAAYGRKKRRQRR SEQ ID NO: 119CGLFEAIEGFIENGWEGMIDGWYGRKKRRQRRRPPQ SEQ ID NO: 120GLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRC SEQ ID NO: 121Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLRKKRRQRRRPPQ-NH2 SEQ ID NO: 122Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLGPGRKKRRQRRRPPQ-NH2 SEQ ID NO: 123Ac-LIRLWSHLIHIWFQNRRLKWKKK-NH2 SEQ ID NO: 124 Ac-RKKRRQRRRPPQQQQQQ-NH2SEQ ID NO: 125 Ac-GLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR-NH2 SEQ ID NO: 126Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLGGGRRRRRRRRR-NH2 SEQ ID NO: 127Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHL-(Peg)12-RKKRRQRRRPPQ-NH2 SEQ ID NO: 128Ac-GLFGAIAGFIENGWEGMIDGWYGLIRLWSHLIWFQNRRLKWLLL-NH2 SEQ ID NO: 129Ac-HHHHHRKKRRQRRRPPQGGGLHLLHHLLHHLHHLLHHLLHLLHHLLHHL-NH2 SEQ ID NO: 130Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHL-(Peg)2-RKKRRQRRRPPQ-NH2 SEQ ID NO: 131Ac-LHLLHHLLHHLHHLLHHLLLLHHLLHHLGGGRQIKIWFQNRRMKWKKGG-NH2 SEQ ID NO: 132Ac-KLLKLLLKLWLKLLKLLLKLLGGGRKKRRQRRRPPQ-NH2 SEQ ID NO: 133Ac-LHHLLHHLLHLLHHLLHHLHHLLHHLLHLC-NH2 all (D) SEQ ID NO: 134Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHL-PEG6-RKKRRQRRRPPQC-NH2 SEQ ID NO: 135Ac-GLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRC-NH2 SEQ ID NO: 136CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR all (D) SEQ ID NO: 137CGLFEAIEGFIENGWEGMIDGWYGYGRRRRRRRRR-NH2 SEQ ID NO: 138YGRKKRRQRRGLFEAIEGFIENGWEGMIDGWYGC-NH2 SEQ ID NO: 139CGVFVLGFLGFLATAGSYGRKKRRQRR-NH2 SEQ ID NO: 140CGLFKAIAKFIKGGWKGLIKGWYG-NH2 SEQ ID NO: 141CGLFEAIEGFIENGWEGMIDGWYGYGRKKR SEQ ID NO: 142CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRYGRKKRRQRR SEQ ID NO: 143CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRYGRKKRRQRR SEQ ID NO: 144CGLFEAIKGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 145CGLFEAIHGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 146CGLFEAIRGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 147CGLFEAIDGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 148CRLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 149CGGGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 150CGLFEAIEGFIENGWEGMIDGWYGGGGYGRKKRRQRR SEQ ID NO: 151CGLFEAIEGFIENGWEGMIDGWYG-(PEG)11-YGRKKRRQRR SEQ ID NO: 152CFLGFLLGVGSAIASGIAVSKVLHL SEQ ID NO: 153CGVFVLGFLGFLATAGSAMGARSLTLSAYGRKKRRQRR SEQ ID NO: 154Ac-GLWRALWRLLRSLWRLLWRA-mercaptoethylamide SEQ ID NO: 155C-Nle-LFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 156CELFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 157CGFFGAIAGFLEGGWEGMIAGWHGYGRKKRRQRR SEQ ID NO: 158CFLGFLLGVGSAIASGIAVSKVLHLYGRKKRRQRR SEQ ID NO: 159GLFEAIEGFIENGWEGLAEALAEALEALAAGGSC SEQ ID NO: 160CGLFEAIEGFIENGWEGMIDGWYGLHLLHHLLHHLHHLLHHLLHLLHHLLHHL SEQ ID NO: 161CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRLHLLHHLLHHLHHLLHHLLHLL SEQ ID NO: 162HHLLHHL CGLFGAIAGFIEGGWTGMIDGWYGYGRKKRRQRR SEQ ID NO: 163CGLFGAIAGFIEGGWQGMVDGWYGYGRKKRRQRR SEQ ID NO: 164CGLFGAIAGFIENGWQGLIDGWYGYGRKKRRQRR SEQ ID NO: 165CGLFGAIAGFIENGWEGLVDGWYGYGRKKRRQRR SEQ ID NO: 166CGLFGAIAGFIEGGWSGMIDGWYGYGRKKRRQRR SEQ ID NO: 167CGLFGAIAGFIEGGWPGLVAGWYGYGRKKRRQRR SEQ ID NO: 168CGLFGAIAGFIENGWEGMVDGWYGYGRKKRRQRR SEQ ID NO: 169CGLFGAIAGFIEGGWPGLINGWYGYGRKKRRQRR SEQ ID NO: 170CGLFGAIAGFIENGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 171CGLFGAIAGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 172CGLFGAIAGFIENGWEGMIDGWYGSSKKKK SEQ ID NO: 173CGLFGAIAGFIENGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 174CGLFEAIEGFIENGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 175CGLFGAIAGFIENGWEGLIEGWYGGGRKKRRQRR SEQ ID NO: 176CGLFEAIEGFIENGWEGMIDGWYGGGRKKRRQRR SEQ ID NO: 177CGLFEAIAGFIENGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 178CGLFEAIAEFIENGWEGLIEGWYGGRKKRRQRR SEQ ID NO: 179CGLFEAIEGFIENGWEGMIDGWYGRKKRRQRRR SEQ ID NO: 180 CKLLKLLLKLWLKLLKLLLKLLSEQ ID NO: 181 CKLLKLLLKLWLKLLKLLLKLLYGRKKRRQRR SEQ ID NO: 182GLFEAIEGFIENGWEGMIDGWYGC SEQ ID NO: 183CVLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 184CSLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 185CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQ SEQ ID NO: 186CGLFEAIEGFIENGWEGMIDGWYGYGRKKRR SEQ ID NO: 187CGLFEAIEGFIENGWEGMIDGWYGYGKKKKKQKK SEQ ID NO: 188CGLFEAIEGFIENGWEGMIDGWYGGLFEAIEGFIENGWEGMIDGWYG SEQ ID NO: 189CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRGLFEAIEGFIENGWEGMIDG SEQ ID NO: 190WYGYGRKKRRQRR RRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLGC SEQ ID NO: 191CRRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLG SEQ ID NO: 192GLFEAIEGFIENGWEGMIDGWYGYGRK-K(D)-RRQRR SEQ ID NO: 193GLFEAIEGFIENGWEGMIDGWYGYGRKK-R(D)-RQRR SEQ ID NO: 194GL-F(D)-EAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 195GLF-E(D)-AIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 196CGLFEAIEGFIENGWEGMIDGWYG SEQ ID NO: 197 CYGRKKRRQRR SEQ ID NO: 198YGRKKRRQRRC SEQ ID NO: 199 RRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLGC all(D)SEQ ID NO: 200 CRRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLG all(D) SEQ ID NO: 201CGLFEAIEGFIENGWEGMIDGAYGYGRKKRRQRR SEQ ID NO: 202CGLFEALLELLESLWELLLEAWYGYGRKKRRQRR SEQ ID NO: 203CGLFEAIEGFNENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 204CGLFEAIEGFIENEWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 205K(stearoyl)GLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRC SEQ ID NO: 206CGLFEAIK(stearoyl)GFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 207CGLFEAIKGFIENGWEGMIDGWYGYGRK(stearoyl)KRRQRR SEQ ID NO: 208CGLFEAIEGFIENPWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 209(stearyl)GLFEAIEGFIENPWEGMIDGWYGYGRKKRRQRRC SEQ ID NO: 210CGLFGAIAGFIEGGWPGLINGWYGYGRKKRRQRRLHLLHHLLHHLHHLLHHLLHLL SEQ ID NO: 211HHLLHHL CGLFGAIAGFIEGGWPGLINGWYGYGRKKRRQRRLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 212 CGLFEAIAGFIEGGWPGLINGWYGYGRKKRRQRR SEQ ID NO: 213CGLEEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 214CGLFNAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 215CGLFAAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 216CGLFEAIENFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 217CGLFEAIEKFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 218CGLFEAIEGFAENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 219CGLFEAIEGFIENWWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 220CGLFEAIEGFIENNWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 221CGLFEAIEGFIENGEEGMIDGWYGYGRKKRRQRR SEQ ID NO: 222CGLFEAIEGFIENGWAGMIDGWYGYGRKKRRQRR SEQ ID NO: 223CGLFEAIEGFIENGWNGMIDGWYGYGRKKRRQRR SEQ ID NO: 224CGLFEAIEGFIENGWGGMIDGWYGYGRKKRRQRR SEQ ID NO: 225CGLFEAIEGFIENGWEGMIDAWYGYGRKKRRQRR SEQ ID NO: 226CGLFEAIEGFIENGWLGMIDGWYGYGRKKRRQRR SEQ ID NO: 227CGLFEAIEGFIENGWKGMIDGWYGYGRKKRRQRR SEQ ID NO: 228CGLFEAIEGFIENGWEGMIDKWYGYGRKKRRQRR SEQ ID NO: 229CGLFEAIEGFIENGWEGMIDEWYGYGRKKRRQRR SEQ ID NO: 230CGLFEAIEGFIENGWEGMIDGLYGYGRKKRRQRR SEQ ID NO: 231CGLFEAIEGFIENGWEGMIDGNYGYGRKKRRQRR SEQ ID NO: 232CGLFEAIEGFIENGWEGMIDGKYGYGRKKRRQRR SEQ ID NO: 233CGLFEAIEGFIENGWEGMIDGEYGYGRKKRRQRR SEQ ID NO: 234CGLFEALEELLEGGWEGLIEAWYGYGRKKRRQRR SEQ ID NO: 235CELFGAIWEFIEGGWEGLIEAWYGYGRKKRRQRR SEQ ID NO: 236CGLFEALEEFIEGGWEGLLEAWYGYGRKKRRQRR SEQ ID NO: 237CGLFEALEEFIENGWEGLLEAWYGYGRKKRRQRR SEQ ID NO: 238CGLFEAIEGFIESGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 239CGLFEAIEEFIEGGWEGLIEAWYGYGRKKRRQRR SEQ ID NO: 240CGLFEAIEGFIENGWEGLIDAWYGYGRKKRRQRR SEQ ID NO: 241CGLFEAIEGFILNGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 242CGLFEAIEGFIKNGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 243CGLFEAIEGFIGNGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 244CGLFEAIEGFIELGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 245CGLFEAIEGFIEKGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 246CGLFEAIAEFIEGGWEGLIEGWYGYGRKKRRQRR SEQ ID NO: 247 CRGWEVLKYWWNLLQYSEQ ID NO: 248 CRGWEVLKYWWNLLQYYGRKKRRQRR SEQ ID NO: 249CGLFGAIAGFIENGWEGMIDGWYGFRYGRKKRRQRR SEQ ID NO: 250Ac-CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR-CO2H SEQ ID NO: 251CGLLEALEGLLENGWEGLLEAWYGYGRKKRRQRR SEQ ID NO: 252CLRHLLRHLLRHLRHLLRHLRHLLRHLLRH SEQ ID NO: 253CGIFEAIEGFIENGWEGIIDGWYGYGROORRQRR (O = ornithine) SEQ ID NO: 254CGIGAVLKVLTTGLPALISWIKRKRQQ SEQ ID NO: 255 CGIGAVLKVLTTGLPALISWIHHHHQQSEQ ID NO: 256 CGAFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 257Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLRRRRR SEQ ID NO: 258CGLFGAIWGFIENWWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 259CGLFGAIEGFIENGWKGLIDAWYGYGRKKRRQRR SEQ ID NO: 260CGLFEAIAGFIENGWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 261GLFEAIEGFIENGWKGLIDWWYGYGRKKRRQRRC SEQ ID NO: 262YGRKKRRQRRGLFEAIEGFIENGWKGLIDAWYGC SEQ ID NO: 263YGRKKRRQRRGLFEAIEGFIENGWKGLIDWWYGC SEQ ID NO: 264CGLFHAIHGFIENGWHGLIDWWYGYGRKKRRQRR SEQ ID NO: 265CGLFEAIEGFIENGWKGLIDWWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 266CGLFKALLKLLKSLWKLLLKAWYGYGHKKHHQHR SEQ ID NO: 267CGLFKALLKLLKSLWKGLLKAWYGYGHKKHHQHR SEQ ID NO: 268CGLAKALLKLLKSLWKGLIEAWYGYGRKKRRQRR SEQ ID NO: 269 CGIFGAIAGFIKNIWSEQ ID NO: 270 CIFGAIAGFIKNIWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 271CGIFGAIAGFIKNIWEGLIDGYGRKKRRQRR SEQ ID NO: 272CGIFGAIAGFIKNIWKGLIDAWYGYGRKKRRQRR SEQ ID NO: 273CIFGAIAGFIKNIWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 274 CLFGAIAGFIKNIWSEQ ID NO: 275 CGL(R5)EAIEGF(S8)ENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 276CGLFEA(S5)EGF(S5)ENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 277CGLFEAIEGFIENGWEGAIDGWYGYGRKKRRQRR SEQ ID NO: 278CGLFEAIEGFIENGWEGEIDGWYGYGRKKRRQRR SEQ ID NO: 279CGIFGAIAGFIKNGWEGMVDWYGYGRKKRRQRR SEQ ID NO: 280CGLFEAIAGFIENGWEGMIDGWYGFYGRKKRRQRR SEQ ID NO: 281CGIFGAIAGFIKNGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 282 CIFGAIAGFIKNIWSEQ ID NO: 283 CIFGAIAGFIKNIWYGRKKRRQRR SEQ ID NO: 284CGIFGAIAGFIKNIWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 285CGLFEAIEGFIENGWEGLIEAYGRKKRRQRR SEQ ID NO: 286CGLFEALLGFIENGWEGLIDGYGRKKRRQRR SEQ ID NO: 287CGLFGAIEGFIENGWEGLIDGWYGYGRKKRRQRRR SEQ ID NO: 288CELFGAIEGFIENGWEGMIDGWYGYGRKKRRQRRR SEQ ID NO: 289CGLFEAIEGFIENGWEGMIDGWYGYGHKKHHQHR SEQ ID NO: 290CGLFGAIEGFIEGGWPGLINGWYGYGRKKRRQRRR SEQ ID NO: 291CGLFKALLKLLKSLWKLLLKAYGRKKRRQRR SEQ ID NO: 292CGLFKALLKLLKSLWKLLLKAWYGYGRKKRRQRR SEQ ID NO: 293CGLFRALLRLLRSLWRLLLRAYGRKKRRQRR SEQ ID NO: 294CGLFEAILGFIENGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 295CGLFEAIWEFIENGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 296CGLFEAIEGFIENGWEGMIDGWYGGGGLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 297CGPVEDAITAAIGRVADTVGTYGRKKRRQRR SEQ ID NO: 298 CMDGTLFPGDDDLAIPATEFFSTKASEQ ID NO: 299 CGLFEALEEFIEGGWEGLLEAWYGYGRKKRRQRR SEQ ID NO: 300CGLFEALEEFIENGWEGLLEAWYGYGRKKRRQRR SEQ ID NO: 301CELFGAIWEFIEGGWEGLIEAYGRKKRRQRR SEQ ID NO: 302CGLFEAIEGFIEEGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 303CGLFEAIAEFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 304CGLFEAIAEFIEGLWEGLIEGWYGYGRKKRRQRR SEQ ID NO: 305CGLLEALEGLLESLWEGLLEAWYGYGRKKRRQRR SEQ ID NO: 306CGLFEAIEGFIENGWEGMIDIWYGYGRKKRRQRR SEQ ID NO: 307CGLFEAIEGFIENGWRGMIDGWYGYGRKKRRQRR SEQ ID NO: 308CGLFEAIEGFIENGWDGMIDGWYGYGRKKRRQRR SEQ ID NO: 309CGLFEAIEGFIENHWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 310CGLFEAIEGFIENWWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 311GLFEAIEGFIENGWKGLIDAWYGYGRKKRRQRRC SEQ ID NO: 312CGLFEAIEGFIENGWKGMIDAWYGYGRKKRRQRR SEQ ID NO: 313CGLFEAIEGFIENGWKGMIDWWYGYGRKKRRQRR SEQ ID NO: 314CGLAEAIEGFIENGLKGLIDWWYGYGRKKRRQRR SEQ ID NO: 315RRQRRKKRGYGYWGDILGEWGNEIFGEIAEFLGC all(D) SEQ ID NO: 316CRRQRRKKRGYGYWGDILGEWGNEIFGEIAEFLG all(D) SEQ ID NO: 317CGLFEAIEGFIENGWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 318CGFFEAIEGFIENGLKGLIDAWYGYGRKKRRQRR SEQ ID NO: 319CGLFEAIEGFIENGLKGLIDAWYGYGRKKRRQRR SEQ ID NO: 320CELFGAIEGFIENGWKGLIDAWYGYGRKKRRQRR SEQ ID NO: 321CGLFKAIKGFIKNGWKGLIKAWYGYGRKKRRQRR SEQ ID NO: 322CGLAEALLELLESLWKGLIEAYGRKKRRQRR SEQ ID NO: 323CGIFGAIEGFIENGWKGLIDAWYGYGRKKRRQRR SEQ ID NO: 324CGIAGAIAGFIKNIWEGLIDWWYGYGRKKRRQRR SEQ ID NO: 325CGIAGAIAGFIKNIWKGLIDAWYGYGRKKRRQRR SEQ ID NO: 326CGIFGAIAGFIKNIWEGLIDGWYGKKKKKKKKK SEQ ID NO: 327CG(R5)FEAIEG(S8)IENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 328CGLFEAIEGF(R5)ENGWEG(S8)IDGWYGYGRKKRRQRR SEQ ID NO: 329GLFEAIEGFIENGWEGMIDGWYGCYGRKKRRQRR SEQ ID NO: 330GLFEAIEGFIENGWEGMIDGWYGGCGYGRKKRRQRR SEQ ID NO: 331GLLEALEGLLENGWEGLLDGWYGYGRKKRRQRR SEQ ID NO: 332 CFFGAIWEFIRNILSEQ ID NO: 333 CIFGAIAGFIRSIL SEQ ID NO: 334CGLFEEIEEFIENGWEGLIDWWYGYGRKKRRQRR SEQ ID NO: 335 CGFFGAIWEFIKSILSEQ ID NO: 336 GFFGAIWEFIKSILC SEQ ID NO: 337CGLFEALEGFIENGWEGLLDGWYGYGROORRQRR (O = ornithine) SEQ ID NO: 338CGLFEALLELLENGWELLLEAWYGYGRKKRRQRR SEQ ID NO: 339CGLFEALLELLENGWELLLDGWYGYGRKKRRQRR SEQ ID NO: 340CALFEAIEAFIENGWEAMIDAWYGYGRKKRRQRR SEQ ID NO: 341CGLFGAIWGFIENGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 342CGLFEAIEELIENLWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 343CGLFEEIEGFIENGWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 344CGLFEEIEGFIENGWKGLIDWWYGYGHKKHHQHR SEQ ID NO: 345CFFGAIWEFIKNILKGLIDGWYG SEQ ID NO: 346 CGIFGAIAGFIRSIL SEQ ID NO: 347CGLFEEIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 348CGLFEAIEGFIENGWEGMIDGWNGYGRKKRRQRR SEQ ID NO: 349AGYLLGKINLKALAALAKKILHHHHHHKKKKKKC SEQ ID NO: 350Bis CGLFEAIEGFIENGWEGMIDWWYGYGRKKRRQRR SEQ ID NO: 351CGLFEAIEGFIENGWEGMIDGWYG-(PEG)6-YGRKKRRQRR SEQ ID NO: 352CGIFGAIWNGIKSLFEGLIDGWYGYGRKKRRQRR SEQ ID NO: 353CGIFGAIEGFIENGWEGLIDWWYGYGRKKRRQRR SEQ ID NO: 354CIFGAIAGFIKNIWEGLIDWWYGYGRKKRRQRR SEQ ID NO: 355CGLFEAIEGFIENGWKGLIDGWYGGLFEAIEGFIENGWKGLIDWWYG SEQ ID NO: 356CWEAALAEALAEALAEHLAEALAEALEALAAYGRKKRRQRRK(stearyl) SEQ ID NO: 357CGLFEAIEGFIENGWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 358CGLFEELEELLEEGWEGLLEAYGRKKRRQRR SEQ ID NO: 359CGNFEEIEEFIEEGLRNFIDWWYGYGHKKHHQHR SEQ ID NO: 360CFFGAIWEFIRNILEGLIDWWYGYGRKKRRQRR SEQ ID NO: 361CFFGAIWEFIKNILLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 362CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR all(D) SEQ ID NO: 363CGFFHAFFHFFHSFWHGFFEA SEQ ID NO: 364 CGLFHALLHLLHSLWHGLLHWWYGYGHKKHHQHRSEQ ID NO: 365 CGLFGALLELLESLWEGLLEWYGRKKRRQRR SEQ ID NO: 366CGLFGALLELLESLWEGLLEWYGHKKHHQHR SEQ ID NO: 367 CGLFHALLHLLHSLWKGLLEWWYGFSEQ ID NO: 368 CIFGAIAGFIRSILEGF SEQ ID NO: 369 CGIFGAIAGFIKNIWKGLIDASEQ ID NO: 370 CFFEAIEEFIKNIWK SEQ ID NO: 371CGLFEAIEGFIENGWKGLIDWLAEALAEALEALAA SEQ ID NO: 372 GCGIFGAIAEFIKNIWSEQ ID NO: 373 CIFGAIAEFIKNIWKGLIDW SEQ ID NO: 374CFFGAIWEFIKSILELLLEAYGHKKHHQHRR SEQ ID NO: 375 CWFGAIWEFIKSILSEQ ID NO: 376 CAFGAIWEFIKSIL SEQ ID NO: 377 CFLGAIWEFIKSILSEQ ID NO: 378 CFFGAIWEFIKSIK SEQ ID NO: 379CGFIGAIANLLSKIFEGLIDGWYGYGRKKRRQRR all(D) SEQ ID NO: 380 CFFGAIWEFIKSILSEQ ID NO: 381 CIFGAIAGFIKNIWLHLLHHLLHHLHHLLHHLLHL all(D) SEQ ID NO: 382CFFGAIAEFIKNIW SEQ ID NO: 383 CIFEAIWGFIKNIW SEQ ID NO: 384stearyl-AGYLLGKINLKALAALAKKILHHHHHHKKKKKKC SEQ ID NO: 385CIFEAIAGFIKNIWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 386CGLFEAIEGFIENGWKGLIDWWYGGRPRESGKKRKRKRLKP SEQ ID NO: 387C(b-Ala)GFGEIEEFIENGLKNLIDWWYGYGHKKHHQHR SEQ ID NO: 388C(b-Ala)GFEFIEEFIENGLKNLIDWWYGYGRKKRRQRR SEQ ID NO: 389C(b-Ala)GFEFIEEFIENGLKNLIDWWYGYGHKKHHQHR SEQ ID NO: 390CGGIEEIAGLLSKILKGLIDWWYGYGHKKHHQHR SEQ ID NO: 391CGFIGAIANLLSKIFEGLIDWWYGYGRKKRRQRR SEQ ID NO: 392CGFIGAIAELLEKIFEGLIDWWYGYGRKKRRQRR SEQ ID NO: 393CGFIGAIAELLEKIFEGLIDWWYGYGHKKHHQHR SEQ ID NO: 394CFFGAIWEFIRNILEGLIDWWYGYGHKKHHQHR SEQ ID NO: 395CFFGAIWEFIKSILLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 396CFFGAIWEFIRSILLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 397CGFFGAIWEFIRSILEGFIDWWYGYGYGHKKHHQHR SEQ ID NO: 398CGLFEAIWEFIKSILEGLLEAYGHKKHHQHR SEQ ID NO: 399CGLFEAIWEFIKSILEGLLEAWYGYGHKKHHQHR SEQ ID NO: 400CGIFGAIAGFIKNIWKYGRKKRRQRR SEQ ID NO: 401CGLFEALLELLESLWELLLEAWYGYGHKKHHQHR SEQ ID NO: 402CIFGAIAGFIRNIWKGLIDGWYG SEQ ID NO: 403 CGIFGAIAGFIRNIWKGLIDGWYGSEQ ID NO: 404 CFFGAIWEFIKNILKLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 405CFFGAIWEFIRNILLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 406 CFFGKIWEFIKSILSEQ ID NO: 407 CYGRKKRRQRRGLFEALLELLESLWELLLEA SEQ ID NO: 408FFGAIWEFIKSILC SEQ ID NO: 409 CWWGAIEGFIKSIL SEQ ID NO: 410CFFGAIWEWIKSIL SEQ ID NO: 411 CFFGAIWEFWKSIL SEQ ID NO: 412CFFGAIWEFIKFIL SEQ ID NO: 413 CFFGAIWEFIKKIL SEQ ID NO: 414CFFGAIWEFIKGIL SEQ ID NO: 415 CFFGAIWEFIKLIL SEQ ID NO: 416CFFGAIWEFIKWIL SEQ ID NO: 417 CFFGAIWEFIKSFL SEQ ID NO: 418CFFGAIWEFIKSKL SEQ ID NO: 419 CFFGFIWEFIKSIL SEQ ID NO: 420CIFGAIAGFIKNILKGLIDAF SEQ ID NO: 421 CFFGKIWELWEWIL SEQ ID NO: 422CFFGAIWEFAKSIL SEQ ID NO: 423 CFFGAIWEFIKSAL SEQ ID NO: 424CFFGAIWEFIKSWL SEQ ID NO: 425 CFFGAIWEFIKSILK SEQ ID NO: 426CFFGAIWEFIKSILE SEQ ID NO: 427 CFFKAIWEFIKSIL SEQ ID NO: 428CFFNAIWEFIKSIL SEQ ID NO: 429 CFFGGIWEFIKSIL SEQ ID NO: 430CFFGNIWEFIKSIL SEQ ID NO: 431 CFFGALWEFIKSIL SEQ ID NO: 432CFFGAAWEFIKSIL SEQ ID NO: 433 CGLFHALLHLLHSLWHGLLDG SEQ ID NO: 434CGLFHALLHLLHSLWHGLLEW SEQ ID NO: 435 CGLFHALLHLLHSLWHLLLEASEQ ID NO: 436 CGLFHALLHLLHSLWKLLLEW SEQ ID NO: 437 CKFGAIWEFIKSILSEQ ID NO: 438 CFKGAIWEFIKSIL SEQ ID NO: 439 CFFGAIWKFIKSILSEQ ID NO: 440 CFFGAIWAFIKSIL SEQ ID NO: 441 CFFGAIWLFIKSILSEQ ID NO: 442 CFFGAIWFFIKSIL SEQ ID NO: 443 CFFGAIWNFIKSILSEQ ID NO: 444 CFFGAIWELIKSIL SEQ ID NO: 445 CFFGAIWEAIKSILSEQ ID NO: 446 CGLFEAIEGFIENGWEGLAEALAEALEALAAYGRKKRRQRR SEQ ID NO: 447CIFGAIAGFIKNIWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 448CIFGAIAGFIKNIWEGLIDAWYGYGRKKRRQRR SEQ ID NO: 449CIFGAIAGFIKNIWKGLIDAWYGYGRKKRRQRR SEQ ID NO: 450CIFGAIAGFIKNIWIFGAIAGFIKNIWWYGYGRKKRRQRR SEQ ID NO: 451CGLFGAIAGFIENGWEGLIEGWYG SEQ ID NO: 452CGLFEAIEGFIENGWEGLIDGWYGYGOOOOOQRR (O = ornithine) SEQ ID NO: 453CGLFEAIEGFIENGWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 454CGLFEAIEGFIENGWEGLIDGWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 455CYGHKKHHQHRGLFEAIEGFIENGWKGLIDWWYG SEQ ID NO: 456CYGHKKHHQHRGLFEAIEEFIENGWEGLIDGWYG SEQ ID NO: 457CGLFEAIEGFIENGWKGLIDGWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 458CGLFEAIEGFIENGWHGMIDGWYGYGRKKRRQRR SEQ ID NO: 459IFGIDDLIIGLLFVAIVEAGIGGYLLGSYGRKKRRQRRC SEQ ID NO: 460CGFFGEIAELIEEGLKGLIDWWNG SEQ ID NO: 461 CGLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 462 CFFGAIWEFIHSIL all (D) SEQ ID NO: 463 CFFGAIWEFIHNILSEQ ID NO: 4.64 CFFGAIWEFIHSIFK SEQ ID NO: 4.65 CGIFEAIAGLLKWIFKSEQ ID NO: 466 CGIFELIAGLLKNIFK SEQ ID NO: 467CGIFEAIAGLLKSILKK(stearyl) SEQ ID NO: 468 CGIFGAIAGLLKSILKK(stearyl)SEQ ID NO: 469 CIFGAIAGFIKNILKGL all (D) SEQ ID NO: 470CIFGAIAGFIKNILKGLIDGWWYG SEQ ID NO: 471 CIFGAIAGFIKNIWHGLISEQ ID NO: 472 CIFGAIAGFIKNILKGLK(stearyl) SEQ ID NO: 473GLGKLINKIFGAIAGFIC all (D) SEQ ID NO: 474 CGIFEAIAGLLKNIFDSEQ ID NO: 475 CGIFEAIAGLLKNIFE SEQ ID NO: 476 CGIFEAIAGLLKNIFRSEQ ID NO: 477 CGIFEAIAGLLKNIFH SEQ ID NO: 478CGIFEAIAGLLKNIFO (O = ORNITHINE) SEQ ID NO: 479 CGIFEAIAGLLKNIFNSEQ ID NO: 480 CGIFEAIAGLLKNIFCit (Cit = citrulline) SEQ ID NO: 481CGIFEAIWGLLKNIFK SEQ ID NO: 482 CGIFGAIWGLLKNIFK SEQ ID NO: 4.83CIFGAIAGLLKNIFK SEQ ID NO: 484 CIFEAIAGLLKNIFK SEQ ID NO: 485CFFGAIAGLLKNIFK SEQ ID NO: 486 CFFEAIAGLLKNIFK SEQ ID NO: 487CGFFEAIAGLLKNIFK SEQ ID NO: 488 CIFGAIAGFIKNIWEGLI all (D)SEQ ID NO: 489 CIFGAIAGLLKNIFK all(D) SEQ ID NO: 490CGLFGEIEELIEEGLENLIDWWNG all(D) SEQ ID NO: 491CGNFGEIEELIEEGLENLIDWWNG all(D) SEQ ID NO: 492CGFFGEIAELIEEGLKGLIDWWNG all(D) SEQ ID NO: 493 CGLFGEIEELIEEGLENLIDWWNESEQ ID NO: 494 CGFFGAIAGLLKNIFK SEQ ID NO: 495CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 496CGLFELIEGFIEWGWEGMIDGWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 497CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(2H, 2H, 3H, 3H- SEQ ID NO: 498perfluorononanoyl)CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(2H, 2H, 3H, 3 H-perfluoro-10SEQ ID NO: 499 methylundecanoyl)CIFGAIAGFIKNIWEGLIK(2H, 2H, 3 H,3H-perfluorononanoyl) SEQ ID NO: 500CIFGAIAGFIKNIWEGLIK(2H, 2H, 3H, 3H-perfluoro-10 methylundecanoyl)SEQ ID NO: 501 CGLFEAIEGFIEWGWEGMIDGWYGYGRKKRRQRRK(2H, 2H, 3H, 3H-SEQ ID NO: 502 perfluorononanoyl)CGLFEAIEGFIEWGWEGMIDGWYGYGRKKRRQRRK(2H, 2H, 3H, 3H-perfluoro-10SEQ ID NO: 503 methylundecanoyl)CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRK(2H, 2H, 3H, 3H- SEQ ID NO: 504perfluorononanoyl)CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRK(2H, 2H, 3H, 3H-perfluoro-10SEQ ID NO: 505 methylundecanoyl)CFFGAIWEFIHSILK(2H, 2H, 3H, 3H-perfluorononanoyl) SEQ ID NO: 506CFFGAIWEFIHSILK(2H, 2H, 3H, 3H-perfluoro-10 methylundecanoyl)SEQ ID NO: 507 CIFGAIAGFIKNILKGLK(2H, 2H, 3H, 3H-perfluorononanoyl)SEQ ID NO: 508CIFGAIAGFIKNILKGLK(2H, 2H, 3H, 3H-perfluoro-10 methylundecanoyl)SEQ ID NO: 509 CFFGAIWEFIRNILEGFK(2H, 2H, 3H, 3H-perfluorononanoyl)SEQ ID NO: 510CFFGAIWEFIRNILEGFK(2H, 2H, 3H, 3H-perfluoro-10 methylundecanoyl)SEQ ID NO: 511 CGLFGEIEELIEEGLENLIDWWNQ SEQ ID NO: 512 CGIFGAIAGLLKSALKSEQ ID NO: 513 CGIFEAIAGLLKSIWK SEQ ID NO: 514 CGIFEAIAGLLKSILKSEQ ID NO: 515 CGIFEAIAGLLONIFK (O = Ornithine) SEQ ID NO: 516CGIFEAIAGLLKNILKGLIDGWYG SEQ ID NO: 517 CGIFGAIAGLLKNILKGLIDGWYGSEQ ID NO: 518 CGIFGAIAGLLKNIFKGLIDGWYG SEQ ID NO: 519 CGIFGAIWELWEWILKSEQ ID NO: 520 CGIFEAIWELWEWILK SEQ ID NO: 521CGLFEAIEGFIENGWEGMIDGWYGK(stearyl) SEQ ID NO: 522(stearyl)GLFEAIEGFIENGWEGMIDGWYGC SEQ ID NO: 523 CFLE-Aib-LWKLLEHLLSEQ ID NO: 524 CFLE-Aib-LWELLEHLL SEQ ID NO: 525 CFLEALWE-Aib-LEHLLSEQ ID NO: 526 CFLE-Aib-LWE-Aib-LEHLL SEQ ID NO: 527 CFLE-Aib-LWEALEKLFSEQ ID NO: 528 (stearyl)IFGAIAGFIKNIWEGLIC SEQ ID NO: 529CIFGAIAGFIKNIWEGLIK(stearyl) SEQ ID NO: 530 (stearyl)FFGAIWEFIKSILCSEQ ID NO: 531 CFFGAIWEFIKSILK(stearyl) SEQ ID NO: 532(stearyl)FFGAIWEFIHSILC SEQ ID NO: 533 CFFGAIWEFIHSILK(stearyl)SEQ ID NO: 534 (stearyl)GIFEAIAGLLKNIFKC SEQ ID NO: 535CGIFEAIAGLLKNIFK(stearyl) SEQ ID NO: 536 CGIFEAIAGLLKNIFKK(stearyl)SEQ ID NO: 537 (stearyl)IFGAIAGFIKNILKGLC SEQ ID NO: 538CIFGAIAGFIKNILKGLK(stearyl) SEQ ID NO: 539 CIFGAIAGFIKNILKGLSEQ ID NO: 540 CGLFGEIEELIEEGLENLIDWWNS SEQ ID NO: 541CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 542CGFFGEIAELIEEGLKNLIDWWNG SEQ ID NO: 543CGLFEAIEGFIENGWKGMIDGWYGYGRKKRRQRR SEQ ID NO: 544CGLFEAIEGFIEWGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 545CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 546 CIFGAIAGFIKNIWEGLISEQ ID NO: 547 CGLFGEIEELIEEGLENLIDWWNG SEQ ID NO: 548CGLFEEIEGFIENGWEGLIDWWYGYGHKKGGQHR SEQ ID NO: 549CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 550CGLFEALLELLESLWELLEAYGRKKRRQRR SEQ ID NO: 551CGLFEALLELLESLWELLEAYGRKKRRQRR SEQ ID NO: 552 CFFGAIWEFIRNILEGFSEQ ID NO: 553 CFFGAIWEFIRNILEGFK(stearyl) SEQ ID NO: 554CIFGAIAGFIKNIWEGLIK(lauryl) SEQ ID NO: 555 (lauryl)FFGAIWEFIKSILCSEQ ID NO: 556 CFFGAIWEFIKSILK(lauryl) SEQ ID NO: 557(lauryl)FFGAIWEFIHSILC SEQ ID NO: 558 CFFGAIWEFIHSILK(lauryl)SEQ ID NO: 559 (lauryl)GIFEAIAGLLKNIFKC SEQ ID NO: 560CGIFEAIAGLLKNIFK(lauryl) SEQ ID NO: 561 CFFGAIWEFIRNILEGFK(lauryl)SEQ ID NO: 562 (lauryl)GLFEAIEGFIENGWEGMIDGWYGC SEQ ID NO: 563CGLFEAIEGFIENGWEGMIDGWYGK(lauryl) SEQ ID NO: 564CGKFTIVFPHNQKGNWKNVPSNYHYK(stearyl) SEQ ID NO: 565CMDGTLFPGDDDLAIPATEFFSTKAK(stearyl) SEQ ID NO: 566CNPVENYIDEVLNEVLWPNINSSNK(stearyl) SEQ ID NO: 567CVTPHHVLVDEYTGEWVDSQFK(stearyl) SEQ ID NO: 568CIFGIDDLIIGLLFVAIVEAGIGGYLLGSK(stearyl) SEQ ID NO: 569CGAAIGLAWIPYFGPAAEK(stearyl) SEQ ID NO: 570CFAGVVLAGAALGVATAAQITAGIALHK(stearyl) SEQ ID NO: 571CFLGFLLGVGSAIASGIAVSKVLHLK(stearyl) SEQ ID NO: 572CFFGAVIGTIALGVATSAQITAGIALAK(stearyl) SEQ ID NO: 573CFFGAVIGTIALGVATAAQITAGIALAK(stearyl) SEQ ID NO: 574GLFEAIAGFIENGGWEGMIDGGGK(stearyl) SEQ ID NO: 575GLFKAIAKFIKGGWKGLIKGWYGK(stearyl) SEQ ID NO: 576GLFHAIAHFIHGGWHGLIHGWYGK(stearyl) SEQ ID NO: 577CGLFEAIAEFIENGWEGLIEGWYGK(stearyl) SEQ ID NO: 578CGFFGAIAGFLEGGWEGMIAGWHGK(stearyl) SEQ ID NO: 579CFAGVVIGLAALGVATAAQVTAAVALVKK(stearyl) SEQ ID NO: 580CAVGIVGAMFLGFLGAAGSTMGAVSLTLTVQAK(stearyI) SEQ ID NO: 581CGVFVLGFLGFLATAGSAMGARSLTLSAK(stearyl) SEQ ID NO: 582CVPFVLGFLGFLGAAGTAMGAAATALTVK(stearyl) SEQ ID NO: 583CAVPVAVWLVSALAMGAGVAGGITGSMSLASGK(stearyl) SEQ ID NO: 584CGLASTLTRWAHYNALIRAFK(stearyl) SEQ ID NO: 585CGPVEDAITAAIGRVADTVGTK(stearyl) SEQ ID NO: 586CGLGQMLESMIDNTVREVGGAK(stearyl) SEQ ID NO: 587CGLFEAIEGFIENGWEGMIDGWYGFK(stearyl) SEQ ID NO: 588(D)-(cgl)FEAIEGFIENGWEGMIDGWYGYGRKKRR(D)-(qrr) SEQ ID NO: 589CGODLEAIEGFIENGWEGMIDWYGYGRKKRRQRR SEQ ID NO: 590CIFGIDDLIIGLLFVAIVEAGIGGYLLGS(stearyl) SEQ ID NO: 591CVTVLALGALAGVGVG(stearyl) SEQ ID NO: 592CLLGRRGWEVLKYWWNLLQYWSQEL(stearyl) SEQ ID NO: 593 CGIFEAIAGLLKNIFDSEQ ID NO: 594 CGIFEAIAGLLKNIFE SEQ ID NO: 595 CGIFEAIAGLLKNIFRSEQ ID NO: 596 CGIFEAIAGLLKNIFH SEQ ID NO: 597CGIFEAIAGLLKNIFO (O =ORNITHINE) SEQ ID NO: 598 CGIFEAIAGLLKNIFNSEQ ID NO: 599 CGIFEAIAGLLKNIFCit (Cit = citrulline) SEQ ID NO: 600CGIFGAIWGLLKNIFK SEQ ID NO: 601 CIFEAIAGLLKNIFK SEQ ID NO: 602CFFEAIAGLLKNIFK SEQ ID NO: 603 CGFFEAIAGLLKNIFK SEQ ID NO: 604CGIFEAIAGLLKNIFKG SEQ ID NO: 605 CGIFEAIAGLLKNIFKGL SEQ ID NO: 606CGIFEAIAGLLKNIFKGLI SEQ ID NO: 607 CGIFEAIAGLLKNIFKGLID SEQ ID NO: 608CGIFEAIAGLLKNIFKGLIDG SEQ ID NO: 609 CGIFEAIAGLLKNIFKGLIDGFSEQ ID NO: 610 CGIFEAIAGLLKNIFKGLIDGWYG SEQ ID NO: 611 CGIFEAIAGLLKNIFKSEQ ID NO: 612 CGIFEAIAGLLKSILK SEQ ID NO: 613 CGIFEAIAGLLKNIFKASEQ ID NO: 614 CGIFEAIAGLLKNIFKL SEQ ID NO: 615 CGIFEAIAGLLKNIFKWSEQ ID NO: 616 CGIFEAIAGLLKNIFKF SEQ ID NO: 617 CGIFEAIAGLLKNAFKSEQ ID NO: 618 CGIFGAIAGLLKNAFK SEQ ID NO: 619CGIFEAIAGLLONIFO (o = Ornithine) SEQ ID NO: 620CGIFEAIAGLLKNIFKGIFEAIAGLLKNIFK SEQ ID NO: 621CGIFEAIAGLLKNIFKFFGAIWEFIHSIL SEQ ID NO: 622CFFGAIWEFIHSILGIFEAIAGLLKNIFK SEQ ID NO: 623 CFFGAIWEFIHSILFFGAIWEFIHSILSEQ ID NO: 624 CFFGAIWEFIHSILGFFGAIWEFIHSIL SEQ ID NO: 625CGIFEAIAGLLKNIFKGIFEAIAGLLKNIFK SEQ ID NO: 626CGIFEAIAGLLKNIFKFFGAIWEFIHSIL SEQ ID NO: 627CFFGAIWEFIHSILGIFEAIAGLLKNIFK SEQ ID NO: 628 CGLFHALLHLLHSLWHLLLEASEQ ID NO: 629 CGLFHALLHLLHSLWHLLLEAK(stearyl) SEQ ID NO: 630CGLFHALLHLLHSLWHLLLEAK(stearyl) SEQ ID NO: 631(stearyl)GLFHALLHLLHSLWHLLLEAC SEQ ID NO: 632 CFFGNIWEFIKSILSEQ ID NO: 633 CFFGAIWLFIKSIL SEQ ID NO: 634 CFFGAIWNFIKSILSEQ ID NO: 635 CFFGAIWGFIKSIL SEQ ID NO: 636 CFLGALFKALSKLLSEQ ID NO: 637 CFLGALFHALSKLL SEQ ID NO: 638 CFLGALFKALSHLLSEQ ID NO: 639 CFLGALFHALSHLL SEQ ID NO: 640 FLGALFKALSKLLCSEQ ID NO: 641 FLGALFHALSKLLC SEQ ID NO: 642 FLGALFKALSHLLCSEQ ID NO: 643 FLGALFHALSHLLC SEQ ID NO: 644 CFLGALFKALKSLLSEQ ID NO: 645 CFLGALFHALKSLL SEQ ID NO: 646 CFLGALFKALHSLLSEQ ID NO: 647 CFLGALFHALHSLL SEQ ID NO: 648 FLGALFKALKSLLCSEQ ID NO: 649 FLGALFHALKSLLC SEQ ID NO: 650 FLGALFKALHSLLCSEQ ID NO: 651 FLGALFHALHSLLC SEQ ID NO: 652 CGIFGAIAGFIKNIWKGLIDWSEQ ID NO: 653 CGLFEAIEGFIENGWEG-Nle-IDGWYGYGRKKRRQRR SEQ ID NO: 654CGLFEAIEGFIENGLKGLIDWWYGYGRKKRRQRR SEQ ID NO: 655CGLFEAIEGFIENAWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 656CGLFEAIEGFIENGWEGMIDLWYGYGRKKRRQRR SEQ ID NO: 657 CRLLRLLLRLWRRLLRLLRSEQ ID NO: 658 CGIFGAIEGFIENGWKGLIDAWYGYRKKRRQRR SEQ ID NO: 659CFFGAIWEFAHGIL SEQ ID NO: 660 CFFGAIWEFARGILEGF SEQ ID NO: 661FFGAIWEFAHGILC SEQ ID NO: 662 FFGAIWEFARGILEGFC SEQ ID NO: 663CFFGAIWEFAHSIL SEQ ID NO: 664 FFGAIWEFAHSILC SEQ ID NO: 665CFFGAIWEFARSILK SEQ ID NO: 666 FFGAIWEFARSILKC SEQ ID NO: 667CGIFEAIAGLAKNIFK SEQ ID NO: 668 GIFEAIAGLAKNIFKC SEQ ID NO: 669CGIFEAIAGLAKNIFH SEQ ID NO: 670 CGIFEAIAGLAHNIFH SEQ ID NO: 671CGIFEAIAGLAHNIFK SEQ ID NO: 672 GIFEAIAGLAKNIFHC SEQ ID NO: 673GIFEAIAGLAHNIFHC SEQ ID NO: 674 CFLGALWKALSKLL SEQ ID NO: 675CFLGALWHALSKLL SEQ ID NO: 676 CFLGALWKALSHLL SEQ ID NO: 677CFLGALWHALSHLL SEQ ID NO: 678 FLGALWKALSKLLC SEQ ID NO: 679FLGALWHALSKLLC SEQ ID NO: 680 FLGALWKALSHLLC SEQ ID NO: 681FLGALWHALSHLLC SEQ ID NO: 682 CGIFGAIAGLLKNAFK SEQ ID NO: 683CIFEAIAGLLKNAFK SEQ ID NO: 684 CIFGAIAGLLKNAFK SEQ ID NO: 685CIFEAIWEFIKNIW SEQ ID NO: 686 CIFEAIAEFIKNIW SEQ ID NO: 687CIFGAIWEFIKNIW SEQ ID NO: 688 CIFGAIAEFIKNIW SEQ ID NO: 689CGIFGIAIGFKINIW SEQ ID NO: 690 CGIFEAIAGLLHNIFK SEQ ID NO: 691CGIFEAIWGLLHNIFK SEQ ID NO: 692 CGFFEAIAGLLHNIFK SEQ ID NO: 693CGIFEAIAALLKNIFK SEQ ID NO: 694 CGIFEAIEGLLKNIFK SEQ ID NO: 695CGIFEAIAGFFKNIFK SEQ ID NO: 696 CGIFEAIAGWWKNIFK SEQ ID NO: 697CGIFEAIAGLLKNIWK SEQ ID NO: 698 CGIFEAIAELLKNIFK SEQ ID NO: 699CGIFGAIAGLLKSALK SEQ ID NO: 700 CGIFEAIAGLLKSIWK SEQ ID NO: 701CGIFEAIAGLLKSILK SEQ ID NO: 702 CGIFEAIAGLLKNIFKGLIDA SEQ ID NO: 703CGIFEAIAGLLKNIFKGLIDAF SEQ ID NO: 704 CGIFEAIAGLLKNIFKGLIDAWYGSEQ ID NO: 705 CGIFEAIAGLLKNIFKGLIDAWYGF SEQ ID NO: 706CGIFEAIAGLLKNIFKGLIDGWYGF SEQ ID NO: 707 CGIFEAIAGLLKNIFKGLIDWSEQ ID NO: 708 CGIFEAIAGLLKNIFKGLIDWF SEQ ID NO: 709CGIFEAIAGLLKNIFKGLIDWWYG SEQ ID NO: 710 CGIFEAIAGLLKNIFKGLIDWWYGFSEQ ID NO: 711 CGIFELIAGLLKNIFK SEQ ID NO: 712 CGIFEAIAGLLKWIFKSEQ ID NO: 713 CGIFELIAGLLKWIFK SEQ ID NO: 714 CGIFELIAGLLKNIFKGSEQ ID NO: 715 CGIFEAIAGLLKWIFKG SEQ ID NO: 716 CGIFELIAGLLKWIFKGSEQ ID NO: 717 CGLFEALLGLLESLWK SEQ ID NO: 718 CGIFEAIAELLKNIFKSEQ ID NO: 719 CGIFEALLGLLKSLWK SEQ ID NO: 720 CGIFEALLELLKSLWKSEQ ID NO: 721 CGIFEAIAGLLKNIFK SEQ ID NO: 722 CEIFEAIAGLLKNIFKSEQ ID NO: 723 CEIFGAIAGLLKNIFK SEQ ID NO: 724 CGLFEAIAGLLKNLFKSEQ ID NO: 725 CGIWEAIAGLLKNIWK SEQ ID NO: 726 CGLFGAIAGLLKNLFKSEQ ID NO: 727 CGIWGAIAGLLKNIWK SEQ ID NO: 728 CGIFDAIAGLLKNIFKSEQ ID NO: 729 CGIFDAIWGLLKNIFK SEQ ID NO: 730 CGIFGGIGGLLKNIFKSEQ ID NO: 731 CAIFAAIAALLKNIFK SEQ ID NO: 732 CGIFEAIAGLLKNIFSEQ ID NO: 733 CGIFEAIAGLLKNI SEQ ID NO: 734 CGIFEAIAGLLKNSEQ ID NO: 735 CGIFEAIAGLLK SEQ ID NO: 736 CVIFEAIAGLLKNIFKSEQ ID NO: 737 CSIFEAIAGLLKNIFK SEQ ID NO: 738 CGIFEEIAGLLKNIFKSEQ ID NO: 739 CGIFEEIWGLLKNIFK SEQ ID NO: 740 CGIFEAIEELLKNIFKSEQ ID NO: 741 CGIFEAIAGLWKNIFK SEQ ID NO: 742 CGIFEAIAGLLENIFKSEQ ID NO: 743 CGIFEAIAGLLWNIFK SEQ ID NO: 744 CGIFEAIAGLLKEIFKSEQ ID NO: 745 CGIFEAIAGLLKNILK SEQ ID NO: 746 CGIFEAIAGLLRNIFKSEQ ID NO: 747 CGIFEAIAGLLKSIFK SEQ ID NO: 748 CGIFEAIAGLLKNILKSEQ ID NO: 749 CGFFGAIWEFIKSILK SEQ ID NO: 750 CGFFEAIWEFIKSILKSEQ ID NO: 751 CGFFGAIWGLLKSILK SEQ ID NO: 752 CGFFEAIWGLLKSILKSEQ ID NO: 753 CGFFEAIAGLLKSILK SEQ ID NO: 754 CGFFGAIAGLLKSILKSEQ ID NO: 755 CGIFEAIAGLLKNIFEGLI SEQ ID NO: 756 CGIFEAIWGLLKNIFKGLISEQ ID NO: 757 CGIFEAIWGLLKNIFEGLI SEQ ID NO: 758CGIFEAIAGLLKNILKGLIDGWYG SEQ ID NO: 759 CGIFGAIAGLLKNILKGLIDGWYGSEQ ID NO: 760 CGIFGAIAGLLKNIFKGLIDGWYG SEQ ID NO: 761 CGIFGAIWELWEWILKSEQ ID NO: 762 CGIFEAIWELWEWILK SEQ ID NO: 763 CIFGAIWELWEWILKSEQ ID NO: 764 CIFEAIWELWEWILK SEQ ID NO: 765 CGIFEAIAELWKNIFKSEQ ID NO: 766 CGIFEAIAELWENIFK SEQ ID NO: 767 CGIFEAIAELWKWIFKSEQ ID NO: 768 CGIFEAIAELWEWIFK SEQ ID NO: 769 CGIFEAIAGLLKNILKGLIDWWYGSEQ ID NO: 770 CGIFGAIAGLLKNILKGLIDWWYG SEQ ID NO: 771CGIFGAIAGLLKNIFKGLIDWWYG SEQ ID NO: 772 CGIFEAIAGLLKNILKGLIDGWYGFSEQ ID NO: 773 CGIFGAIAGLLKNILKGLIDGWYGF SEQ ID NO: 774CGIFGAIAGLLKNIFKGLIDGWYGF SEQ ID NO: 775 CGIFGAIAELLEKIFE SEQ ID NO: 776CGIFEAIAELLEKIFE SEQ ID NO: 777 CGFIGAIAELLEKIFE SEQ ID NO: 778CGIFGAIAELLEKIFK SEQ ID NO: 779 CGIFEAIAELLEKIFK SEQ ID NO: 780CGFIGAIAELLEKIFK SEQ ID NO: 781 CGLFHALLHLLHSLWHLLLEA SEQ ID NO: 782GLFHALLHLLHSLWHGLLEAC SEQ ID NO: 783 GFFHAFFHFFHSFWHGFFEACSEQ ID NO: 784 GLFHALLHLLHSLWHLLLEAC SEQ ID NO: 785CGLFHALLHLLHSLWHGLLEAK(stearyl) SEQ ID NO: 786CGFFHAFFHFFHSFWHGFFEAK(stearyl) SEQ ID NO: 787CGLFHALLHLLHSLWHLLLEAK(stearyl) SEQ ID NO: 788(stearyl)GLFHALLHLLHSLWHGLLEAC SEQ ID NO: 789(stearyl)GFFHAFFHFFHSFWHGFFEAC SEQ ID NO: 790(stearyl)GLFHALLHLLHSLWHLLLEAC SEQ ID NO: 791 CGFFHAFFHFFHSFWHFFFEASEQ ID NO: 792 CGFFHAFFHFFHSFWHLFFEA SEQ ID NO: 793CGLFHALLHLLHSLWHGLLEW SEQ ID NO: 794 CGLFHALLHLLHSLWHLLLEWSEQ ID NO: 795 CGFFHAFFHFFHSFWHGFFEW SEQ ID NO: 796 CFFGAIWEFAKSILSEQ ID NO: 797 CFFGAIWEFAHSIL SEQ ID NO: 798 CFFGAIWEFAHGILSEQ ID NO: 799 CFFGAIWEFIHSILK SEQ ID NO: 800 CFFGAIWEFIHSILHSEQ ID NO: 801 CFFGAIWEFIHSILD SEQ ID NO: 802 CFFGAIWEFIHSILRSEQ ID NO: 803 CFFGAIWEFIHSILO SEQ ID NO: 804 CFFGAIAEFIHSILSEQ ID NO: 805 CIFGAIWEFIHSIL SEQ ID NO: 806 CGIFGAIWEFIHSILSEQ ID NO: 807 CFFGAIWEFIHSILE SEQ ID NO: 808 CFFGAIWEFIHSILEGSEQ ID NO: 809 CFFGAIWEFIHSILEGL SEQ ID NO: 810 CFFGAIWEFIHSILEGLISEQ ID NO: 811 CFFGAIWEFIHSILEGLID SEQ ID NO: 812 CFFGAIWEFIHSILEGLIDGSEQ ID NO: 813 CFFGAIWEFIHSILEGLIEA SEQ ID NO: 814 CFFGAIWEFIHSILEGLIDWSEQ ID NO: 815 CFFGAIWEFIHSILEGLIDGWYG SEQ ID NO: 816CFFGAIWEFIHSILEGLIDGWYGF SEQ ID NO: 817 FFGAIWEFIHSILC SEQ ID NO: 818CFWGAIWEFIHSIL SEQ ID NO: 819 CFFGAIWEFIHSILKGLIDW SEQ ID NO: 820CAFGKIWEFAHSIL SEQ ID NO: 821 CAFGKIWEFIHSIL SEQ ID NO: 822CFFGKIWEFIHSIL SEQ ID NO: 823 CAFGAIWEFIHSIL SEQ ID NO: 824CAFGAIWEFAHSIL SEQ ID NO: 825 CGFFGAIAGLLHNIFK SEQ ID NO: 826CFFGAIAGLLHNIFK SEQ ID NO: 827 CGFFEAIEGLLHNIFK SEQ ID NO: 828CFFEAIAGLLHNIFK SEQ ID NO: 829 CFFEAIWGLLHNIFK SEQ ID NO: 830CGFFGAIAELLHNIFK SEQ ID NO: 831 CFFGAIAELLHNIFK SEQ ID NO: 832CGFFEAIAELLHNIFK SEQ ID NO: 833 CFFEAIAELLHNIFK SEQ ID NO: 834CFFGAIWELLHNIFK SEQ ID NO: 835 CFFEAIWELLHNIFK SEQ ID NO: 836CFFGAIWEFIHSILFFGAIWEFIHSIL SEQ ID NO: 837CFFGAIWEFIHSILGGGFFGAIWEFIHSIL SEQ ID NO: 838CFFGAIWEFIHSILGFFGAIWEFIHSIL SEQ ID NO: 839 GGLFEALLELLESLWELLLEWSEQ ID NO: 840 GGFFEAFFEFFESFWEFFFEA SEQ ID NO: 841GGLFEALLELLESLWEGLLEA SEQ ID NO: 842 CGLFHALLHLLHSLWHLLLHASEQ ID NO: 843 CGLFEALLHLLHSLWHLLLEA SEQ ID NO: 844CGLFEALLELLHSLWHLLLEA SEQ ID NO: 845 CGLFEALLHLLESLWHLLLEASEQ ID NO: 846 CGLFEALLHLLHSLWELLLEA SEQ ID NO: 847CGLFHALLELLHSLWHLLLEA SEQ ID NO: 848 CGLFHALLHLLESLWHLLLEASEQ ID NO: 849 CGLFHALLHLLHSLWELLLEA SEQ ID NO: 850CGLFHALLELLESLWHLLLEA SEQ ID NO: 851 CGLFHALLELLHSLWELLLEASEQ ID NO: 852 CGLFHALLHLLESLWELLLEA SEQ ID NO: 853CGLFEALLHLLESLWELLLEA SEQ ID NO: 854 CGLFEALLELLHSLWELLLEASEQ ID NO: 855 CGLEALLELLESLWHLLLEA SEQ ID NO: 856 CGLFHALLELLESLWELLLEASEQ ID NO: 857 CFFGAIWEFIHSILHLLLEA SEQ ID NO: 858 CFFGAIWEFIHSILKLLLEASEQ ID NO: 859 CGFFGAIWEFIHSILGFFGAIWEFIHSIL SEQ ID NO: 860CFFGAIWEFAHSILFFGAIWEFAHSIL SEQ ID NO: 861 CFFGAIWEFAHSILGFFGAIWEFAHSILSEQ ID NO: 862 CGFFGAIWEFAHSILGFFGAIWEFAHSIL SEQ ID NO: 863CFFGAIWEFIHSILGLFEAIEGFIENGWEGMIDG SEQ ID NO: 864CFFGAIWEFIHSILGLFEAIEGFIENGWEGMIDGWYG SEQ ID NO: 865CFFGAIWEFIHSILGLFEAIEGFIENGWEGMIDGWYGF SEQ ID NO: 866CFFGALLEFIHSILELLLEA SEQ ID NO: 867 CGLFGALLEFIHSILELLLEA SEQ ID NO: 868CGFFGALLEFIHSILELLLEA SEQ ID NO: 869 CFFGALLEFIHSLWELLLEA SEQ ID NO: 870CGLFGALLEFIHSLWELLLEA SEQ ID NO: 871 CGFFGALLEFIHSLWELLLEASEQ ID NO: 872 CIFGAIAGFIKNIWK(stearyl) SEQ ID NO: 873(stearyl)IFGAIAGFIKNIWC SEQ ID NO: 874 CFFGAIWEFIKSILK(stearyl)SEQ ID NO: 875 (stearyl)FFGAIWEFIKSILC SEQ ID NO: 876CFFGAIWEFIHSILK(stearyl) SEQ ID NO: 877 (stearyl)FFGAIWEFIHSILCSEQ ID NO: 878 CIFGAIAGFIKNIWEGLIK(stearyl) SEQ ID NO: 879(stearyl)IFGAIAGFIKNIWEGLIC SEQ ID NO: 880 (stearyl)IFGAIAGFIKNILKGLCSEQ ID NO: 881 (stearyl)GIFGAIAGFIKNILKGLC SEQ ID NO: 882CIFGAIAGFIKNILKGLK(stearyl) SEQ ID NO: 883 CGLFGAIAGFIVNGWVGMIDGSEQ ID NO: 884 CGLFGAIAGFIVNGWVGMIDGWYG SEQ ID NO: 885CGLFEAIEGFIVNGWVGMIDGWYG SEQ ID NO: 886 CGLFGAIAGFIVNGWVGMIDGWYGFSEQ ID NO: 887 CGLFEAIEAGFIVNGWVGMIDGWYGF SEQ ID NO: 888CGLFGAIAGFIVNGWVGMIDGWYGK(stearyl) SEQ ID NO: 889CGLFEAIEGFIVNGWVGMIDGWYGK(stearyl) SEQ ID NO: 890(stearyl)GLFGAIAGFIVNGWVGMIDGWYGC SEQ ID NO: 891(stearyl)GLFEAIEGFIVNGWVGMIDGWYGC SEQ ID NO: 892(stearyl)GLFGAIAGFIVNGWVGMIDGWYGFC SEQ ID NO: 893(stearyl)GLFEAIEAGFIVNGWVGMIDGWYGFC SEQ ID NO: 894 CFFGAIWGLLHSILHSEQ ID NO: 895 CFFGAIWELLHSIL SEQ ID NO: 896 CFFGAIWELLHSILHSEQ ID NO: 897 CFFGAIWGLLHSILK SEQ ID NO: 898 CFFGAIWELLHSILKSEQ ID NO: 899 CGLFGALLHLLHSLWELLLEA SEQ ID NO: 900CGLFGALLELLHSLWELLLEA SEQ ID NO: 901 CFFGAIWEFIHSILELLLEA SEQ ID NO: 902CFFGAIWEFIHSILHGLLEA SEQ ID NO: 903 CFFGAIWEFIHSILEGLLEA SEQ ID NO: 904CGFFGAIWEFIHSILHLLLEA SEQ ID NO: 905 CGFFGAIWEFIHSILELLLEASEQ ID NO: 906 CGFFGAIWEFIHSILHGLLEA SEQ ID NO: 907CGFFGAIWEFIHSILEGLLEA SEQ ID NO: 908 CGFFGAIAGLLHSIL SEQ ID NO: 909CGFFGAIWGLLHSIL SEQ ID NO: 910 CGFFGALLGLLHSIL SEQ ID NO: 911CFFGAIWEFAKSAL SEQ ID NO: 912 CIFGAIAGFIHNILKGL SEQ ID NO: 913CFFGAIAGFIKNILKGL SEQ ID NO: 914 CIFGAIWGFIKNILKGL SEQ ID NO: 915CIFGAIWGFIHNILKGL SEQ ID NO: 916 CIFGAIAGLLKNILKGL SEQ ID NO: 917CIFGAIAGLLHNILKGL SEQ ID NO: 918 CIFEAIAGFIKNILKGL SEQ ID NO: 919CIFEAIAGFIHNILKGL SEQ ID NO: 920 CGNFGEIAELIEEGLKNLIDWWNG SEQ ID NO: 921CGFFGEIAELIEEGLENLIDWWNG SEQ ID NO: 922 CGNFGEIEELIEEGLKNLIDWWNGSEQ ID NO: 923 CGNFGEIAELIEEGLENLIDWWNG SEQ ID NO: 924CGFFGEIEELIEENGENLIDWWNG SEQ ID NO: 925 CGFFGAIEELIEEGLKNLIDWWNGSEQ ID NO: 926 CGFFGAIAELIEEGLKNLIDWWNG SEQ ID NO: 927CGFFGEIAELIEEGLKNLIDWWNGF SEQ ID NO: 928 GFFGEIAELIEEGLKNLIDWWNGCSEQ ID NO: 929 GNWWDILNKLGEEILEAIEGFFGC SEQ ID NO: 930CGNWWDILNKLGEEILEAIEGFFG SEQ ID NO: 931 CGFLGEIAELIEEGLKNLIDWNGSEQ ID NO: 932 CGFFGEIWELIEEGLKNLIDWNG SEQ ID NO: 933CGFFGEIAELWEEGLKNLIDWNG SEQ ID NO: 934 CGFFGEIAELIWEGLKNLIDWNGSEQ ID NO: 935 CGFFGEIAELIEWGLKNLIDWNG SEQ ID NO: 936CGFFGEIAELIEEGLRNLIDWNG SEQ ID NO: 937 CGFFGEIAELIEEGLDNLIDWNGSEQ ID NO: 938 CGFFGEIAELIEEGLKNLNDWNG SEQ ID NO: 939CGFFGEIEELIEEGLKNLIDWNG SEQ ID NO: 940 CGFLGEIEELIEEGLKNLIDWNGSEQ ID NO: 941 CGFFGLIEELIEEGLKNLIDWNG SEQ ID NO: 942CGFFGEIAELIEEGLKNLIDWNGK(stearyl) SEQ ID NO: 943(stearyl)GFFGEIAELIEEGLKNLIDWWNGC SEQ ID NO: 944CFFGAIWEFAKSILK(stearyl) SEQ ID NO: 945 CGFFGAIWEFAKSIL SEQ ID NO: 946CFFGKIWEFIKSILK(stearyl) SEQ ID NO: 947 (stearyl)FFGKIWEFIKSILCSEQ ID NO: 948 CFFGAIWEFIKSIAK(stearyl) SEQ ID NO: 949(stearyl)FFGAIWEFIKSIAC SEQ ID NO: 950 (stearyl)FFGAIWEFAKSILCSEQ ID NO: 951 CFFGGIWEFIKSILK(stearyl) SEQ ID NO: 952(stearyl)FFGGIWEFIKSILC SEQ ID NO: 953 CFFKAIWEFIKSILK(stearyl)SEQ ID NO: 954 (stearyl)FFKAIWEFIKSILC SEQ ID NO: 955CFFGAIWEAIKSILK(stearyl) SEQ ID NO: 956 (stearyl)FFGAIWEAIKSILCSEQ ID NO: 957 CFFKAIWEFAKSIL SEQ ID NO: 958 CFFKAIWEFAHSILSEQ ID NO: 959 CFFKAIWEFAKSILK(stearyl) SEQ ID NO: 960(stearyl)FFKAIWEFAKSILC SEQ ID NO: 961 CFFKAIWEFAHSILK(stearyl)SEQ ID NO: 962 CGLFGEIAELIEEGLENLIDWWNG SEQ ID NO: 963CGLFGEIEELIEEGLKNLIDWWNG SEQ ID NO: 964 CFFGAIWEFAKSILK(stearyl)SEQ ID NO: 965 CGLFGEIEELIEEGLKGLIDWWNG SEQ ID NO: 966CGLFGEIAELIEEGLKNLIDWWNG SEQ ID NO: 967 CGLFGEIAELIEEGLEGLIDWWNGSEQ ID NO: 968 GLFGEIEELIEEGLENLIDWWNGC SEQ ID NO: 969(stearyl)GLFGEIEELIEEGLENLIDWNGC SEQ ID NO: 970CGLFGEIEELIEEGLENLIDWWNGK(stearyl) SEQ ID NO: 971CGNWWDILNELGEEILEEIEGFLG SEQ ID NO: 972 CALFGEIEELIEEGLENLIDWWNGSEQ ID NO: 973 CELFGEIEELIEEGLENLIDWWNG SEQ ID NO: 974CSLFGEIEELIEEGLENLIDWWNG SEQ ID NO: 975 CNLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 976 CVLFGEIEELIEEGLENLIDWWNG SEQ ID NO: 977CGFFGEIEELIEEGLENLIDWWNG SEQ ID NO: 978 CGVFGEIEELIEEGLENLIDWWNGSEQ ID NO: 979 CGIFGEIEELIEEGLENLIDWWNG SEQ ID NO: 980CGWFGEIEELIEEGLENLIDWWNG SEQ ID NO: 981 CGYFGEIEELIEEGLENLIDWWNGSEQ ID NO: 982 CGLLGEIEELIEEGLENLIDWWNG SEQ ID NO: 983CGLVGEIEELIEEGLENLIDWWNG SEQ ID NO: 984 CGLIGEIEELIEEGLENLIDWWNGSEQ ID NO: 985 CGLWGEIEELIEEGLENLIDWWNG SEQ ID NO: 986CGLYGEIEELIEEGLENLIDWWNG SEQ ID NO: 987 CGLFEEIEELIEEGLENLIDWWNGSEQ ID NO: 988 CGLFAEIEELIEEGLENLIDWWNG SEQ ID NO: 989CGLFNEIEELIEEGLENLIDWWNG SEQ ID NO: 990 CGLFSEIEELIEEGLENLIDWWNGSEQ ID NO: 991 CGLFGAIEELIEEGLENLIDWWNG SEQ ID NO: 992CGLFGDIEELIEEGLENLIDWWNG SEQ ID NO: 993 CGLFGNIEELIEEGLENLIDWWNGSEQ ID NO: 994 CGLFGSIEELIEEGLENLIDWWNG SEQ ID NO: 995CGLFGELEELIEEGLENLIDWWNG SEQ ID NO: 996 CGLFGEVEELIEEGLENLIDWWNGSEQ ID NO: 997 CGLFGEFEELIEEGLENLIDWWNG SEQ ID NO: 998CGLFGEWEELIEEGLENLIDWWNG SEQ ID NO: 999 CGLFGEYEELIEEGLENLIDWWNGSEQ ID NO: 1000 CGLFGEIAELIEEGLENLIDWWNG SEQ ID NO: 1001CGLFGEIGELIEEGLENLIDWWNG SEQ ID NO: 1002 CGLFGEILELIEEGLENLIDWWNGSEQ ID NO: 1003 CGLFGEIVELIEEGLENLIDWWNG SEQ ID NO: 1004CGLFGEISELIEEGLENLIDWWNG SEQ ID NO: 1005 CGLFGEIEDLIEEGLENLIDWWNGSEQ ID NO: 1006 CGLFGEIENLIEEGLENLIDWWNG SEQ ID NO: 1007CGLFGEIESLIEEGLENLIDWWNG SEQ ID NO: 1008 CGLFGEIEALIEEGLENLIDWWNGSEQ ID NO: 1009 CGLFGEIEGLIEEGLENLIDWWNG SEQ ID NO: 1010CGLFGEIEEVIEEGLENLIDWWNG SEQ ID NO: 1011 CGLFGEIEEIIEEGLENLIDWWNGSEQ ID NO: 1012 CGLFGEIEEFIEEGLENLIDWWNG SEQ ID NO: 1013CGLFGEIEEAIEEGLENLIDWWNG SEQ ID NO: 1014 CGLFGEIEEYIEEGLENLIDWWNGSEQ ID NO: 1015 CGLFGEIEEWIEEGLENLIDWWNG SEQ ID NO: 1016CGLFGEIEELVEEGLENLIDWWNG SEQ ID NO: 1017 CGLFGEIEELLEEGLENLIDWWNGSEQ ID NO: 1018 CGLFGEIEELFEEGLENLIDWWNG SEQ ID NO: 1019CGLFGEIEELAEEGLENLIDWWNG SEQ ID NO: 1020 CGLFGEIEELYEEGLENLIDWWNGSEQ ID NO: 1021 CGLFGEIEELWEEGLENLIDWWNG SEQ ID NO: 1022CGLFGEIEELIDEGLENLIDWWNG SEQ ID NO: 1023 CGLFGEIEELINEGLENLIDWWNGSEQ ID NO: 1024 CGLFGEIEELISEGLENLIDWWNG SEQ ID NO: 1025CGLFGEIEELIEDGLENLIDWWNG SEQ ID NO: 1026 CGLFGEIEELIEYGLENLIDWWNGSEQ ID NO: 1027 CGLFGEIEELIESGLENLIDWWNG SEQ ID NO: 1028CGLFGEIEELIEQGLENLIDWWNG SEQ ID NO: 1029 CGLFGEIEELIENGLENLIDWWNGSEQ ID NO: 1030 CGLFGEIEELIEEALENLIDWWNG SEQ ID NO: 1031CGLFGEIEELIEENLENLIDWWNG SEQ ID NO: 1032 CGLFGEIEELIEESLENLIDWWNGSEQ ID NO: 1033 CGLFGEIEELIEEQLENLIDWWNG SEQ ID NO: 1034CGLFGEIEELIEEGWENLIDWWNG SEQ ID NO: 1035 CGLFGEIEELIEEGVENLIDWWNGSEQ ID NO: 1036 CGLFGEIEELIEEGIENLIDWWNG SEQ ID NO: 1037CGLFGEIEELIEEGFENLIDWWNG SEQ ID NO: 1038 CGLFGEIEELIEEGAENLIDWWNGSEQ ID NO: 1039 CGLFGEIEELIEEGYENLIDWWNG SEQ ID NO: 1040CGLFGEIEELIEEGLRNLIDWWNG SEQ ID NO: 1041 CGLFGEIEELIEEGLHNLIDWWNGSEQ ID NO: 1042 CGLFGEIEELIEEGLONLIDWWNG SEQ ID NO: 1043CGLFGEIEELIEEGLDNLIDWWNG SEQ ID NO: 1044 CGLFGEIEELIEEGLKNLIDWWNGSEQ ID NO: 1045 CGLFGEIEELIEEGLEGLIDWWNG SEQ ID NO: 1046CGLFGEIEELIEEGLEYLIDWWNG SEQ ID NO: 1047 CGLFGEIEELIEEGLEQLIDWWNGSEQ ID NO: 1048 CGLFGEIEELIEEGLESLIDWWNG SEQ ID NO: 1049CGLFGEIEELIEEGLEALIDWWNG SEQ ID NO: 1050 CGLFGEIEELIEEGLE(Cit)LIDWWNGSEQ ID NO: 1051 CGLFGEIEELIEEGLENMIDWWNG SEQ ID NO: 1052CGLFGEIEELIEEGLENFIDWWNG SEQ ID NO: 1053 CGLFGEIEELIEEGLENIIDWWNGSEQ ID NO: 1054 CGLFGEIEELIEEGLENWIDWWNG SEQ ID NO: 1055CGLFGEIEELIEEGLENVIDWWNG SEQ ID NO: 1056 CGLFGEIEELIEEGLENYIDWWNGSEQ ID NO: 1057 CGLFGEIEELIEEGLEN(Nle)IDWWNG SEQ ID NO: 1058CGLFGEIEELIEEGLENLIDWWNG SEQ ID NO: 1059 CGLFGEIEELIEEGLENLVDWWNGSEQ ID NO: 1060 CGLFGEIEELIEEGLENLFDWWNG SEQ ID NO: 1061CGLFGEIEELIEEGLENLWDWWNG SEQ ID NO: 1062 CGLFGEIEELIEEGLENLYDWWNGSEQ ID NO: 1063 CGLFGEIEELIEEGLENLIEWWNG SEQ ID NO: 1064CGLFGEIEELIEEGLENLINWWNG SEQ ID NO: 1065 CGLFGEIEELIEEGLENLISWWNGSEQ ID NO: 1066 CGLFGEIEELIEEGLENLIQWWNG SEQ ID NO: 1067CGLFGEIEELIEEGLENLIDGWNG SEQ ID NO: 1068 CGLFGEIEELIEEGLENLIDAWNGSEQ ID NO: 1069 CGLFGEIEELIEEGLENLIDFWNG SEQ ID NO: 1070CGLFGEIEELIEEGLENLIDLWNG SEQ ID NO: 1071 CGLFGEIEELIEEGLENLIDIWNGSEQ ID NO: 1072 CGLFGEIEELIEEGLENLIDVWNG SEQ ID NO: 1073CGLFGEIEELIEEGLENLIDWGNG all (D) SEQ ID NO: 1074CGLFGEIEELIEEGLENLIDWANG SEQ ID NO: 1075 CGLFGEIEELIEEGLENLIDWFNGSEQ ID NO: 1076 CGLFGEIEELIEEGLENLIDWING SEQ ID NO: 1077CGLFGEIEELIEEGLENLIDWVNG SEQ ID NO: 1078 CGLFGEIEELIEEGLENLIDWYNGSEQ ID NO: 1079 CGLFGEIEELIEEGLENLIDWWQG SEQ ID NO: 1080CGLFGEIEELIEEGLENLIDWWTG SEQ ID NO: 1081 CGLFGEIEELIEEGLENLIDWWSGSEQ ID NO: 1082 CGLFGEIEELIEEGLENLIDWWEG SEQ ID NO: 1083CGLFGEIEELIEEGLENLIDWW(Cit)G SEQ ID NO: 1084 CGLFGEIEELIEEGLENLIDWWNASEQ ID NO: 1085 CGLFGEIEELIEEGLENLIDWWNN SEQ ID NO: 1086CGLFGEIEELIEEGLENLIDWWNS SEQ ID NO: 1087 CGLFGEIEELIEEGLENLIDWWNYSEQ ID NO: 1088 CGLFGEIEELIEEGLENLIDWWNW SEQ ID NO: 1089 CFFGAIWGLLHSILSEQ ID NO: 1090 CFFGK(stearyl)IWEFIKSIL SEQ ID NO: 1091CFFGK(stearyI)IWEFIHSIL SEQ ID NO: 1092 CFFK(stearyl)AIWEFIKSILSEQ ID NO: 1093 CGFFGAIWGLLHSILK SEQ ID NO: 1094 CGFFEAIWGLLHSILSEQ ID NO: 1095 CFFGAIWGLLKSIL SEQ ID NO: 1096 CGFFGAIWGLLKSILSEQ ID NO: 1097 CFFEAIWGLLKSIL SEQ ID NO: 1098 CGFFEAIWGLLKSILSEQ ID NO: 1099 CFFGAIWGLLHSILKGLIDWWNG SEQ ID NO: 1100CFFGAIWGLLHSILKGLIDGWYG SEQ ID NO: 1101 CGIFGAIAGLLKNIFKGSEQ ID NO: 1102 CGIFGAIAGLLKNIFKA SEQ ID NO: 1103 CGIFGAIAGLLKNIFKLSEQ ID NO: 1104 CGIFGAIAGLLKNIFKW SEQ ID NO: 1105 CGIFGAIAGLLKNIFKFSEQ ID NO: 1106 CGIFGAIAGLLKNIFKN SEQ ID NO: 1107 CGIFGAIAGLLKNIFKESEQ ID NO: 1108 CGIFGAIAGLLKNIFKS SEQ ID NO: 1109CGIFGAIAGLLKNIFK(stearyl) SEQ ID NO: 1110 CGIFGAIAGLLKNIFKK(stearyl)SEQ ID NO: 1111 (stearyl)GIFGAIAGLLKNIFKC SEQ ID NO: 1112CGIFGAIAGLLKNIFK(lauryl) SEQ ID NO: 1113 CGIFGAIAGLLKNIFKK(lauryl)SEQ ID NO: 1114 (lauryl)GIFGAIAGLLKNIFKC SEQ ID NO: 1115CGIFGAIAGLLHNIFK SEQ ID NO: 1116 CGIFGAIAGLLONIFK SEQ ID NO: 1117CGIFGAIAGLLRNIFK SEQ ID NO: 1118 CGIFGAIAGLLENIFK SEQ ID NO: 1119CGIFGAIAGLLDNIFK SEQ ID NO: 1120 CGIFGAIAGLLKNIFH SEQ ID NO: 1121CGIFGAIAGLLKNIFO SEQ ID NO: 1122 CGIFGAIAGLLKINFE SEQ ID NO: 1123CGIFGAIAGLLKNIFD SEQ ID NO: 1124 CGIFGAIAGLLKNIFN SEQ ID NO: 1125CGIFGAIAGLLNNIFK SEQ ID NO: 1126 CGIFGIAIGLLKNIFKGIFGAIAGLLKNIFKSEQ ID NO: 1127 CGIFGAIWGLLKNIFKG SEQ ID NO: 1128 CGIFGAIWGLLKNIFKASEQ ID NO: 1129 CGIFGAIWGLLKNIFKL SEQ ID NO: 1130 CGIFGAIWGLLKNIFKWSEQ ID NO: 1131 CGIFGAIWGLLKNIFKF SEQ ID NO: 1132 CGIFGAIWGLLKNIFKNSEQ ID NO: 1133 CGIFGAIWGLLKNIFKE SEQ ID NO: 1134 CGIFGAIWGLLKNIFKSSEQ ID NO: 1135 CGIFGAIWGLLKNIFK(stearyl) SEQ ID NO: 1136CGIFGAIWGLLKNIFKK(stearyl) SEQ ID NO: 1137 (stearyl)GIFGAIWGLLKNIFKCSEQ ID NO: 1138 CGIFGAIWGLLKNIFK(lauryl) SEQ ID NO: 1139CGIFGAIWGLLKNIFKK(lauryl) SEQ ID NO: 1140 (lauryl)GIFGAIWGLLKNIFKCSEQ ID NO: 1141 CGIFGAIWGLLHNIFK SEQ ID NO: 1142 CGIFGAIWGLLONIFKSEQ ID NO: 1143 CGIFGAIWGLLRNIFK SEQ ID NO: 1144 CGIFGAIWGLLENIFKSEQ ID NO: 1145 CGIFGAIWGLLDNIFK SEQ ID NO: 1146 CGIFGAIWGLLKNIFHSEQ ID NO: 1147 CGIFGAIWGLLKNIFO SEQ ID NO: 1148 CGIFGAIWGLLKINFESEQ ID NO: 1149 CGIFGAIWGLLKNIFD SEQ ID NO: 1150 CGIFGAIWGLLKNIFNSEQ ID NO: 1151 CGIFGAIWGLLNNIFK SEQ ID NO: 1152 CFFGAIWGLLKNIFKSEQ ID NO: 1153 CGFFGAIWGLLKNIFK SEQ ID NO: 1154 CIFGAIWGLLKNIFKSEQ ID NO: 1155 CGIFGAIWIGLLKNIFKGIFGAIWGLLKNIFK SEQ ID NO: 1156CGIFGAIWGLLHNIFH SEQ ID NO: 1157 CGIFGAIWGLLONIFO SEQ ID NO: 1158CGIFGAIAGLLHSILK SEQ ID NO: 1159 CGIFGAIWGLLHSILK SEQ ID NO: 1160CGIFGAIAGLLHSIL SEQ ID NO: 1161 CGIFGAIWGLLHSIL SEQ ID NO: 1162CGIFGAIWELLKNIFK SEQ ID NO: 1163 CGIFGAIWGLLHNIFHGIFGAIWGLLHNIFKSEQ ID NO: 1164 CGIFEAIWGLLHNIFHGIFEAIWGLLHNIFH SEQ ID NO: 1165CGIFEAIWGLLKNIFHGIFEAIWGLLHNIFH SEQ ID NO: 1166CGIFEAIWGLLKNIFKGIFEAIWELLKNIFH SEQ ID NO: 1167CGIFEAIWGLLKNIFHGIFEAIWGLLKNIFH SEQ ID NO: 1168 CGLFEALLELLESLWELLLEAWNGSEQ ID NO: 1169 CGLFEALLELLESLWELLLEWWNG SEQ ID NO: 1170CGLFGELEELLEEGLENLLDWWNG SEQ ID NO: 1171 CGLFGELEELLEEGLENLLEWWNGSEQ ID NO: 1172 CGLFGELEELLEEGWELLLEAWNG SEQ ID NO: 1173CGLFGELEELLEEGWELLLEWWNG SEQ ID NO: 1174 CGLFGELEELLEEGWELLLDWWNGSEQ ID NO: 1175 CGLFGALLELLEEGLENLIDWWNG SEQ ID NO: 1176CGLFEALLELLEEGLENLIDWWNG SEQ ID NO: 1177 CGLFEALLELLESLLENLIDWWNGSEQ ID NO: 1178 CGLFGELAELLEEGLENLLDWWNG SEQ ID NO: 1179GLFGEIEELIEEGLENLIDWWNG SEQ ID NO: 1180 CFFGNIWEFIHSIL SEQ ID NO: 1181CFFGAIWNFIHSIL SEQ ID NO: 1182 CFFGNIWNFIHSIL SEQ ID NO: 1183CGIFGNIWNFIKNIFK SEQ ID NO: 1184 CGIFGNIWNLLKNIFK SEQ ID NO: 1185CGIFGNIWGLLKNIFK SEQ ID NO: 1186 CGIFGNIWNFIKNIFH SEQ ID NO: 1187CGIFGNIWNLLKNIFH SEQ ID NO: 1188 CGIFGNIWGLLKNIFH SEQ ID NO: 1189CGIFENIWNFIKNIFK SEQ ID NO: 1190 CGIFENIWNFIKNIFH SEQ ID NO: 1191CGIFENIWGLLKNIFK SEQ ID NO: 1192 CGIFENIWGLLKNIFH SEQ ID NO: 1193CGIFENIWNLLKNIFK SEQ ID NO: 1194 CGIFENIWNLLKNIFH SEQ ID NO: 1195CGLFGAIAGLLENIFENLIDWWNG SEQ ID NO: 1196 CGLFGAIAGLLNKIFKNLIDWWNGSEQ ID NO: 1197 CGLFGAIAGLLENIFKNLIDWWNG SEQ ID NO: 1198CGLFGAIAGLLKNIFENLIDWWNG SEQ ID NO: 1199 CGLFGAIAGLLKNIFHNLIDWWNGSEQ ID NO: 1200 CLIGAILKVLATGLPTLISWIKNKRKQ SEQ ID NO: 1201CGLLEEIEELLEEGLENLIDWWNG SEQ ID NO: 1202 CGLFEELEELLEEGLENLIDWWNGSEQ ID NO: 1203 CGLFEELEELLEEGLENLIEA SEQ ID NO: 1204CGLFEELEELLEEGLENLIEAWNG SEQ ID NO: 1205 CGLFEELEELLEEGLENLIEWSEQ ID NO: 1206 CGLFEELEELLEEGLENLIEWWNG SEQ ID NO: 1207CGLFEELEELLEEGLENLIDA SEQ ID NO: 1208 CGLFEELEELLEEGLENLIDAWNGSEQ ID NO: 1209 CGLFEELEELLEEGLENLIDW SEQ ID NO: 1210 CFLGALKFALKSLLSEQ ID NO: 1211 CFLGALHFALKSLL SEQ ID NO: 1212 CFLGALKFALHSLLSEQ ID NO: 1213 CFLGALHFALHSLL SEQ ID NO: 1214 FLGALKFALKSLLCSEQ ID NO: 1215 GFLGALKFALKSLLC SEQ ID NO: 1216 CGLFGELEELIEEGLENLLDWWNGSEQ ID NO: 1217 CGLFGEIEELLEEGLENLLDWWNG SEQ ID NO: 1218CGLFGELEELLEEGLENLIDWWNG SEQ ID NO: 1219 CGLFGEIEELIEEGLENLMDWWNGSEQ ID NO: 1220 CGLFGEIEELIEEGLENLEDWWNG SEQ ID NO: 1221CGLFGEIEELIEEGLENLDDWWNG SEQ ID NO: 1222 CGLFGEIEELIEEGLENLNDWWNGSEQ ID NO: 1223 CGLFGEIEELIEEGLENLSDWWNG SEQ ID NO: 1224CGLFGEIEELIEEGLENLQDWWNG SEQ ID NO: 1225 CGLFGEIEELIEEGLENL-CIT-DWWNGSEQ ID NO: 1226 CGLFGEIEELIEELLENLIDWWNG SEQ ID NO: 1227CGLFGEIEELIEEILENLIDWWNG SEQ ID NO: 1228 CGLFGEIEELIEEVLENLIDWWNGSEQ ID NO: 1229 CFLGALWKLLSHLL SEQ ID NO: 1230 CFLGALWKILSHLLSEQ ID NO: 1231 CFLGALWVKVLSHLL SEQ ID NO: 1232 CFLGALWKFLSHLLSEQ ID NO: 1233 CFLEALWKALSHLL SEQ ID NO: 1234 CFLHALWKALSHLLSEQ ID NO: 1235 CFLKALWKALSHLL SEQ ID NO: 1236 CFLNALWKALSHLLSEQ ID NO: 1237 CFLSALWKALSHLL SEQ ID NO: 1238 CFLQALWKALSHLLSEQ ID NO: 1239 CFLEALWEALSHLL SEQ ID NO: 1240 CFLGALWEALSHLLSEQ ID NO: 1241 CFLEALWKLLSHLL SEQ ID NO: 1242 CFLEALWEALEELLSEQ ID NO: 1243 CFLEELWEALEELL SEQ ID NO: 1244 CFLEALWEALEHLLSEQ ID NO: 1245 CFLEELWEALEHLL SEQ ID NO: 1246 CFLEELWELLEELLSEQ ID NO: 1247 CFLEELWELLEHLL SEQ ID NO: 1248CGLFGEIEELLEEGLE-CIT-LIDWWNG SEQ ID NO: 1249CGLFEEIEELLEEGLE-CIT-LIDWWNG SEQ ID NO: 1250CGLFGEIAELLEEGLE-CIT-LlDWWNG SEQ ID NO: 1251CGLFEEIAELLEEGLE-CIT-LIDWWNG SEQ ID NO: 1252CGLFGEIEELLEEGLE-CIT-LVDWWNG SEQ ID NO: 1253CGLFEEIEELLEEGLE-CIT-LVDWWNG SEQ ID NO: 1254CGLFGEIAELLEEGLE-CIT-LVDWWNG SEQ ID NO: 1255CGLFEEIAELLEEGLE-CIT-LVDWWNG SEQ ID NO: 1256CGLFGEIEELLEEGLE-CIT-LIDWWNE SEQ ID NO: 1257CGLFEEIEELLEEGLE-CIT-LIDWWNE SEQ ID NO: 1258CGLFGEIAELLEEGLE-CIT-LIDWWNE SEQ ID NO: 1259CGLFEEIAELLEEGLE-CIT-LIDWWNE SEQ ID NO: 1260CGLFGEIEELLEEGLH-CIT-LIDWWNG SEQ ID NO: 1261CGLFEEIEELLEEGLH-CIT-LIDWWNG SEQ ID NO: 1262CGLFGEIAELLEEGLH-CIT-LlDWWNG SEQ ID NO: 1263CGLFEEIAELLEEGLH-CIT-LIDWWNG SEQ ID NO: 1264CGLFGEIEELLEEGLE-CIT-LVDWWNE SEQ ID NO: 1265CGLFEEIEELLEEGLE-CIT-LVDWWNE SEQ ID NO: 1266CGLFGEIAELLEEGLE-CIT-LVDWWNE SEQ ID NO: 1267CGLFEEIAELLEEGLE-CIT-LVDWWNE SEQ ID NO: 1268 CFFKNIWEFIKSILSEQ ID NO: 1269 CFFKNIWNFIKSIL SEQ ID NO: 1270 CFFKAIWEFIKSILESEQ ID NO: 1271 CFFKAIWEFIKNIFK SEQ ID NO: 1272 CFFKAIWEFIKNIFKESEQ ID NO: 1273 CFFKAIWELLKSIL SEQ ID NO: 1274 CFFKAIWGLLKSILSEQ ID NO: 1275 CFFKAIWEFIKSILK SEQ ID NO: 1276 CFFKNIWGLLKSILSEQ ID NO: 1277 CFFKAIWGLLKNIFK SEQ ID NO: 1278 CFFKAIWELLKNIFKSEQ ID NO: 1279 CFFKNIWGLLKNIFK SEQ ID NO: 1280 CFFKNIWELLKNIFKSEQ ID NO: 1281 CFFKAIWEFIRSIL SEQ ID NO: 1282 CFFKAIWEFIKSLLSEQ ID NO: 1283 CFFKAIWEFIKSAL SEQ ID NO: 1284 CFFKAIWEFIKSIFSEQ ID NO: 1285 CFFKALWEFLKSLL SEQ ID NO: 1286 CIFKAIWEFIKSILSEQ ID NO: 1287 CFFKAIWEFIKSIW SEQ ID NO: 1288 CFFHAIWEFIKSILSEQ ID NO: 1289 CFFEAIWEFIKSIL SEQ ID NO: 1290 CFFKAIAEFIKSILSEQ ID NO: 1291 CFFKAIEEFIKSIL SEQ ID NO: 1292 CFFKAILEFIKSILSEQ ID NO: 1293 CFFKAIFEFIKSIL SEQ ID NO: 1294 CFFKAIWGFIKSILSEQ ID NO: 1295 CFFKAIWHFIKSIL SEQ ID NO: 1296 CFFKAIWKFIKSILSEQ ID NO: 1297 CFFEAIWKFIKSIL SEQ ID NO: 1298 CFFKAIWELIKSILSEQ ID NO: 1299 CFFKALWELLKSLL SEQ ID NO: 1300 CFFKAIWEAIKSILSEQ ID NO: 1301 CFFKAIWEFLKSIL SEQ ID NO: 1302 CFFKAIWEFIHSILSEQ ID NO: 1303 CFFKAIWEFIESIL SEQ ID NO: 1304 CFFKAIWEFIKNILSEQ ID NO: 1305 CFFKAIWEFIKWIL SEQ ID NO: 1306 CFFKAIWEFIKEILSEQ ID NO: 1307 CFFKAIWEFIKGIL SEQ ID NO: 1308 CFFKAIWEFIKSGLSEQ ID NO: 1309 CFFKAIWEFIKSII SEQ ID NO: 1310 CFFKAIWEFIK-CIT-ILSEQ ID NO: 1311 CFFKAIWEFIKSIA SEQ ID NO: 1312 CFFKAIWEFIKQILSEQ ID NO: 1313 CGFFKAIWEFIKSIL SEQ ID NO: 1314 CFFKAIWEFIKSILKGLIDGSEQ ID NO: 1315 CFFKAIWEFIKSILKGLIDGWYG SEQ ID NO: 1316CFFKAIWEFIKSILEGLIDG SEQ ID NO: 1317 CFFKAIWEFIKSILEGLIDGWYGSEQ ID NO: 1318 CFFKAIWEFIKNIFKGLIDG SEQ ID NO: 1319CFFKAIWEFIKNIFKGLIDGWYG SEQ ID NO: 1320 CFFGNIWEFIKSILKGLIDGSEQ ID NO: 1321 CFFGNIWEFIKSILKGLIDGWYG SEQ ID NO: 1322CFFGNIWEFIKSILEGLIDG SEQ ID NO: 1323 CFFGNIWEFIKSILEGLIDGWYGSEQ ID NO: 1324 CFFGNIWEFIKNIFKGLIDG SEQ ID NO: 1325CFFGNIWEFIKNIFKGLIDGEYG SEQ ID NO: 1326 CFFKAIWGLLKSILKGLIDGSEQ ID NO: 1327 CFFKAIWGLLKSILKGLIDGWYG SEQ ID NO: 1328CFFKAIWGLLKSILEGLIDG SEQ ID NO: 1329 CFFKAIWGLLKSILEGLIDGWYGSEQ ID NO: 1330 CFFKAIWGLLKNIFKGLIDG SEQ ID NO: 1331CFFKAIWGLLKNIFKGLIDGWYG SEQ ID NO: 1332 CFFKAIWGLLKNIFEGLIDGSEQ ID NO: 1333 CFFKAIWGLLKNIFEGLIDGWYG SEQ ID NO: 1334CFFKAIWEFIKSILKGLIDGWNG SEQ ID NO: 1335 CFFKAIWEFIKNIFKGLIDGWNGSEQ ID NO: 1336 CIFGAIAGLLKNILKGLIDG SEQ ID NO: 1337CIFGAIAGLLKNILKGLIDGWYG SEQ ID NO: 1338 CFLEALWKALEHLL SEQ ID NO: 1339CFLEALWEALSKLL SEQ ID NO: 1340 CFLEALWEALEKLL SEQ ID NO: 1341CFLEALWEALEHLLK(stearyl) SEQ ID NO: 1342 (stearyl)FLEALWEALEHLLCSEQ ID NO: 1343 (stearyl)GFLEALWEALEHLLC SEQ ID NO: 1344 CFLEALWKALSKLLSEQ ID NO: 1345 CFLEALWEALDHLL SEQ ID NO: 1346 CFLEALWEALTHLLSEQ ID NO: 1347 CFLEALWEALNHLL SEQ ID NO: 1348 CFLEALWEALQHLLSEQ ID NO: 1349 CFLEALWEALEHLLH SEQ ID NO: 1350 CFLEALWEALEHLLKSEQ ID NO: 1351 CFLEALWEALEHLLE SEQ ID NO: 1352 CWLEALEALEHLLSEQ ID NO: 1353 CLLEALWEALEHLL SEQ ID NO: 1354 CFFEALWEALEHLLSEQ ID NO: 1355 CFLEALEEALEHLL SEQ ID NO: 1356 CFLEALAEALEHLLSEQ ID NO: 1357 CFLEALFEALEHLL SEQ ID NO: 1358 CLFEALWEALHHLLSEQ ID NO: 1359 CLFEALWEALKHLL SEQ ID NO: 1360 CFLEALWEALEHGLSEQ ID NO: 1361 CLFEALWEALEHLF SEQ ID NO: 1362 CLFEALWEALEHFLSEQ ID NO: 1363 CLFEALWEALEHLLEGLIDWWYG SEQ ID NO: 1364CLFEALWEALEHLLEGLIDWWNG SEQ ID NO: 1365 CLFEALWEALEHLLENLIDWWNGSEQ ID NO: 1366 CFLEELWELLEKLL SEQ ID NO: 1367 CFLEELWELLEELLESEQ ID NO: 1368 CFLEELWELLEELLELLE SEQ ID NO: 1369 CFLEELWELLEHLLELLDSEQ ID NO: 1370 CFLEELWELLEELLELID SEQ ID NO: 1371 CFLEELWELLEELLELLDSEQ ID NO: 1372 CFLEELWELLEHLLEGLE SEQ ID NO: 1373 CFLEELWELLEHLLEGLDSEQ ID NO: 1374 CFLEELWELLEHLLEEGLI SEQ ID NO: 1375CFLEELWELLEHLLEGLIDWWYG SEQ ID NO: 1376 CFLEELWELLEHLLENLIDWWNGSEQ ID NO: 1377 CFLEALWEALEHLLELLD SEQ ID NO: 1378CGLFGELEELLEEGLENLTDWWNG SEQ ID NO: 1379CGLFGELEELLEEGLENL-(ALLO-I)-DWWNG SEQ ID NO: 1380 CFLEALWEALEHLLELIDSEQ ID NO: 1381 CELFEELEELLEEGLENLIDWWNG SEQ ID NO: 1382CGLFEELEELLEEGLELLIDWWNG SEQ ID NO: 1383 CGLFEELEELLEEGLELLIDWWNKSEQ ID NO: 1384 CGLFEELEELLEEGLENLIDWWNK SEQ ID NO: 1385CGLFGELEELLEEGLENLIDWWNQ SEQ ID NO: 1386 CGLFGELEELLEEGLENLIDWWNESEQ ID NO: 1387 CGLFGELEELLEEGLENLIDWWNN SEQ ID NO: 1388CGLFGELEELLEEGLENLIDWWNS SEQ ID NO: 1389 CGLFEELEELLEEGLENLIDWWNQSEQ ID NO: 1390 AC-CFLEELWELLEHLL SEQ ID NO: 1391 AC-CFLEELWELLEELLSEQ ID NO: 1392 CGLLGEIEELLEEGLENLIDWWNG SEQ ID NO: 1393CGLLAEIEELLEEGLENLIDWWNG SEQ ID NO: 1394 CGLLGEIEELLEEGLENLIDWWNQSEQ ID NO: 1395 CGLLAEIEELLEEGLENLIDWWNQ SEQ ID NO: 1396CGLLEEIEELLEEGLENLIDWWNQ SEQ ID NO: 1397 CGLLGEIEELLEEGLENLIDWWNESEQ ID NO: 1398 CGLLAEIEELLEEGLENLIDWWNE SEQ ID NO: 1399CGLLEEIEELLEEGLENLIDWWNE SEQ ID NO: 1400 CGLLGEIEELLEEGLENLIDWWNSSEQ ID NO: 1401 CGLLAEIEELLEEGLENLIDWWNS SEQ ID NO: 1402CGLLEEIEELLEEGLENLIDWWNS SEQ ID NO: 1403 CGLFAELEELLEEGLENLLEWWNGSEQ ID NO: 1404 CGLFEELEELLEEGLENLLEWWNG SEQ ID NO: 1405CGLFGELEELLEEGLENLLEWWNE SEQ ID NO: 1406 CGLFAELEELLEEGLENLLEWWNESEQ ID NO: 1407 CGLFEELEELLEEGLENLLEWWNE SEQ ID NO: 1408CGLLGELEELLEEGLENLLEWWNG SEQ ID NO: 1409 CGLLGELEELLEEGLENLLEWWNESEQ ID NO: 1410 CGILGEIEELLEEGLENLIDWWNG SEQ ID NO: 1411CGILGEIEELLEEGLENLIDWWNE SEQ ID NO: 1412 CGILGEIEELLEEGLENLIDWWNSSEQ ID NO: 1413 CGILAEIEELLEEGLENLIDWWNG SEQ ID NO: 1414CGILEEIEELLEEGLENLIDWWNG SEQ ID NO: 1415 CIFGAIAELLKNIFK SEQ ID NO: 1416CIFGAIAELLENIFK SEQ ID NO: 1417 CIFGAIAGLLENIFK SEQ ID NO: 1418CFLEELWGLLEHLL SEQ ID NO: 1419 CGILAEIEELLEEGLENLIDWWNQ SEQ ID NO: 1420CGILAEIEELLEEGLENLIDWWNE SEQ ID NO: 1421 CGLFAEIEELLEEGLENLIDWWNQSEQ ID NO: 1422 CGLFAEIEELLEEGLENLIDWWNE SEQ ID NO: 1423CGLFGELEELLEEGLENLLEWWNQ SEQ ID NO: 1424 CGLFAEIAELLEEGLE-CIT-LIDWWNESEQ ID NO: 1425 CGILAEIEELLEEGLENLLEWWNG SEQ ID NO: 1426CGILEEIEELLEEGLENLIDWWNE SEQ ID NO: 1427 CGILEEIEELLEEGLENLIDWWNQSEQ ID NO: 1428 CGLFGEIEELIWEGLENLIDWWNG SEQ ID NO: 1429CGLFGEIAELIWEGLENLIDWWNG SEQ ID NO: 1430 CGLFEEIAELIEEGLENLIDWWNGSEQ ID NO: 1431 CGLFEEIAELIWEGLENLIDWWNG SEQ ID NO: 1432CELFEEIAELIWEGLENLIDWWNG SEQ ID NO: 1433 CELFEEIAELLWEGLENLIDWWNGSEQ ID NO: 1434 CGLFEEIAELLWEGLENLIDWWNG SEQ ID NO: 1435CGLFEELAELLWEGLENLIDWWNG SEQ ID NO: 1436 CELFEELAELLWEGLENLIDWWNGSEQ ID NO: 1437 CELFEELAELLWEGLENLIDWWNS SEQ ID NO: 1438CGLFEELAELLWEGLENLIDWWNS SEQ ID NO: 1439 CGIFEELAELLWEGLENLIDWWNGSEQ ID NO: 1440 CGIFEELAELLWEGLENLIDWWNS SEQ ID NO: 1441CGLFEELEELLEELLENLIDWWNS SEQ ID NO: 1442 CELFEELEELLEELLENLIDWWNSSEQ ID NO: 1443 CELFEELEELLEELLELLIDWWNS SEQ ID NO: 1444CEFLEELEELLEELLENLIDWWNS SEQ ID NO: 1445 CELFEELEELLEHLLENLIDWWNSSEQ ID NO: 1446 CELFEELEELLHELLENLIDWWNS SEQ ID NO: 1447CGLFGELEELLWEGLENLIDWWNG SEQ ID NO: 1448 CGLFGELEELLWEGLHNLIDWWNGSEQ ID NO: 1449 CGLFGELWELLEHGLENLIDWWNG SEQ ID NO: 1450CGL-R6H-GELEEL-S7H-EEGLENLIDWWNG SEQ ID NO: 1451CGLFEAIEGFIENGWEGMIDGWNG SEQ ID NO: 1452 CGLFEAIEGFIENGWEGMIDWWNGSEQ ID NO: 1453 CGLFGAIEGFIENGWEGMIDWWNG SEQ ID NO: 1454CGLFAEIEELLEEGLENLLEWWNG SEQ ID NO: 1455 CGLFAELEELLEEGLENLIDWWNGSEQ ID NO: 1456 CGIFAEIEELLEEGLENLIDWWNG SEQ ID NO: 1457CGLFAEIEELLEEGLENLIDWWNGF SEQ ID NO: 1458 CGLFAEIEELLEEGLENLIDWWNASEQ ID NO: 1459 CGLFAEIEELLEEGLENLIDWWNS SEQ ID NO: 1460CGLFAEIEELLEEGLENLIDWWN-CIT SEQ ID NO: 1461 CGLFGEIAGLLEEGLHNLIDWWNGSEQ ID NO: 1462 CGLFGEIAGLLEQGLHNLIDWWNG SEQ ID NO: 1463CGLFGEIAGLLESGLHNLIDWWNG SEQ ID NO: 1464 CGLFAEIAGLLEQGLHNLIDWWNGSEQ ID NO: 1465 CGLFAEIAGLLEEGLHNLIDWWNG SEQ ID NO: 1466CGLFAEIAGLLESGLHNLIDWWNG SEQ ID NO: 1467 CGIFEAIAGLLEQGLHNLIDWWNGSEQ ID NO: 1488 CGLFGAIAELLEEGLHNLIDWWNG SEQ ID NO: 1469CGLFAAIAELLEEGLHNLIDWWNG SEQ ID NO: 1470 CGIFEAIAGLLKNIFKNLIDWWNGSEQ ID NO: 1471 CGIFGAIWELLEQGLHNLIDWWNG SEQ ID NO: 1472CGLFAELAGLLEQGLHNLIDWWNG SEQ ID NO: 1473 CGILAELAGLLEQGLHNLIDWWNGSEQ ID NO: 1474 CGLFGEIEELLEHLL SEQ ID NO: 1475 CGLFGEIEELLEELLSEQ ID NO: 1476 CGLFGEIEELLEEGL SEQ ID NO: 1477 CGLFGEIEELLEHGLSEQ ID NO: 1478 CGLFHEIEELLEHLL SEQ ID NO: 1479 CFLGALWKALSELLESEQ ID NO: 1480 CGLFGEIWELLEEGL SEQ ID NO: 1481 CGLFGEIWELLEEGLISEQ ID NO: 1482 CGLFGEIWELLEELL SEQ ID NO: 1483 CGLFEEIEELLEELLESEQ ID NO: 1484 CGLFELIEGFIEWGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 1485CIFGAIAGFIKNIWLHLLHHLLHHLHHLLHHLLHL SEQ ID NO: 1486 CEALFGKINAIFIGKLSEQ ID NO: 1487 CEENWIGLFGGGNIWEEEEILDLL SEQ ID NO: 1488 CLELWLEHLFLELESEQ ID NO: 1489 CGNFEEIEGFIENGWEGLIDGWYGYGRKKRRQRR SEQ ID NO: 1490CRGKWYMGFGEIKRQGEGRRYGLFEDWIAENRGI SEQ ID NO: 1491GLFEAIEGFIENGWEGLAELAEALEALAAGGSC SEQ ID NO: 1492GLFGALAEALAEALAEHLAEALAEALEALAAGGSC SEQ ID NO: 1493CGFFGEIAGLLENGLHNLIDWWNG SEQ ID NO: 1494 CGFFGEIAALLENGLENLIDWWNGSEQ ID NO: 1495 CGFFGEIAEFIHSGLKNLIDWWNG SEQ ID NO: 1496CGFFGEIAGLLKNGLKNLIDWWNG SEQ ID NO: 1497 CGFFGEIAGFIKNGLKNLIDWWNGSEQ ID NO: 1498 CGFFGEIAEFIHSILKNLIDWWNG SEQ ID NO: 1499CGFFGEIAGLLKNILKNLIDWWNG SEQ ID NO: 1500 CGFFGEIAGFIKNILKNLIDWWNGSEQ ID NO: 1501 CFLGALFHALSELL SEQ ID NO: 1502 CFLGALWHALSELLSEQ ID NO: 1503 CFLGALWHALSHLL SEQ ID NO: 1504 CFLGALWELLSHLLSEQ ID NO: 1505 CFLGALWKALSHLL SEQ ID NO: 1506 CFLGALWHALSKLLSEQ ID NO: 1507 CFLGALFHLLSHLL SEQ ID NO: 1508 CFLGALFHLLSELLSEQ ID NO: 1509 CFLGALWHLLSHLL SEQ ID NO: 1510 CFLGALWHLLSELLSEQ ID NO: 1511 CFLGALFHALSHLLE SEQ ID NO: 1512 CFLGALFHLLSHLLESEQ ID NO: 1513 CGLFGALFHALSHLLE SEQ ID NO: 1514 CFLGALWKALSHLLSEQ ID NO: 1515 CGLFAEIEELLEEGLENLIDWWNG SEQ ID NO: 1516CGLFGEIEELIEEGLE-Cit-LIDWWNG SEQ ID NO: 1517 CGLFGEIEELIEEGLENLIDWWNESEQ ID NO: 1518 CFFGAIWEFIHSILK(stearyl) SEQ ID NO: 1519CIFGAIAGFIKNIWEGLIK(stearyl) SEQ ID NO: 1520 CGIFEAIAGLLKNIFK(stearyl)SEQ ID NO: 1521 CGIFEAIAGLLKNIFKK(stearyl) SEQ ID NO: 1522CFLGALFHALSHLL SEQ ID NO: 1523 Ac-CIFGAIAGFIKNILKGLIDG SEQ ID NO: 1524CIFGAIAGFIKNILKGLK(stearylL) SEQ ID NO: 1525Ac-CIFGAIAGFIKNILKGLK(stearyl) SEQ ID NO: 1526 CGLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 1527 CFLGALWKALSELLKNLIDWWNG SEQ ID NO: 1528CGFLGALWKALSELLKNLIDWWNG SEQ ID NO: 1529 CFLGALFHALSHLLENLIDWWNGSEQ ID NO: 1530 CGFLGALFHALSHLLENLIDWWNG SEQ ID NO: 1531CGLFGELEGFIENGLKNLIDWWNG SEQ ID NO: 1532 CGLFGELEGLLWHGLKNLIDWWNGSEQ ID NO: 1533 CGLFGELAELLWHGLKNLIDWWNG SEQ ID NO: 1534CGLFGELAELLWQGLKNLIDWWNG SEQ ID NO: 1535 CGLFGELWELLWHGLKNLIDWWNGSEQ ID NO: 1536 CGLFGELWELLWQGLKNLIDWWNG SEQ ID NO: 1537CGLFEELAGLLWHGLKNLIDWWNG SEQ ID NO: 1538 CGLFEELWGLLWHGLKNLIDWWNGSEQ ID NO: 1539 CGLFEELAGLLWQGLKNLIDWWNG SEQ ID NO: 1540CGLFEELWGLLWQGLKNLIDWWNG SEQ ID NO: 1541 CGLFGELAELLWHGLKNLIDWWNKSEQ ID NO: 1542 CGLFEELAELLWHGLKNLIDWWNK SEQ ID NO: 1543CGLFGELAELLWHGLKNLIDWWNH SEQ ID NO: 1544 CGLFEELAELLWHGLKNLIDWWNHSEQ ID NO: 1545 CGLFAELWGLLWQGLKNLIDWWNG SEQ ID NO: 1546CGLFAELWGLLWHGLKNLIDWWNG SEQ ID NO: 1547 CGLFAELWGLLWHGLHNLLDWWNGSEQ ID NO: 1548 CGLFAELAELLWEGLKNLIDWWNG SEQ ID NO: 1549CGLFAELAELLWHGLKNLIDWWNG SEQ ID NO: 1550 CGLFAELELLWQGLKNLIDWWNGSEQ ID NO: 1551 CELFGELAGLLWHGLKNLIDWWNG SEQ ID NO: 1552CLFEALWE-Aib-LEKLF SEQ ID NO: 1553 CFLEALWELLEHLL SEQ ID NO: 1554CFLEALWKALEKLL SEQ ID NO: 1555 CGLF-Aib-EIAGLLEEGLHNLIDWWNGSEQ ID NO: 1556 CGLFGEI-Aib-GLLEEGLHNLIDWWNG SEQ ID NO: 1557CGFFGEIAGLLEE-Aib-LHNLIDWWNG SEQ ID NO: 1558 CGLFGEIAGLLEEGLHNLIDWWN-AibSEQ ID NO: 1559 CGLF-Aib-EIAGLLEE-Aib-LHNLIDWWNG SEQ ID NO: 1560CGFFGEI-Aib-GLLEE-Aib-LHNLIDWWNG SEQ ID NO: 1561CGFFGEI-Aib-ELIWEGLKNLIDWWNG SEQ ID NO: 1562 CGFFGEIAELIWELKNLIDWWN-AibSEQ ID NO: 1563 CGFFAib-EIAELIWE-Aib-LKNLIDWWNG SEQ ID NO: 1564AC-CFLGALWKALSHLL SEQ ID NO: 1565 AC-CFLEELWELLEELLE SEQ ID NO: 1566AC-CLFGALWKALSELL SEQ ID NO: 1567 AC-CGIGAVLKVLTTGLPALISWIKRKRQQSEQ ID NO: 1568 AC-CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 1569AC-CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 1570Ac-CFLGALWKALSHLL SEQ ID NO: 1571 Ac-CFLGALWKALSELL SEQ ID NO: 1572CELFEEIAELLWEGLENLIDWWNG SEQ ID NO: 1573 CGLFGEIAELIWEGLENLIDWWNGSEQ ID NO: 1574 CGLFGEIEELLEEGLENLIDWWNG SEQ ID NO: 1575CGLFAELAELLWEGLENLIDWWNG SEQ ID NO: 1576 CGLFAELAELLEEGLENLIDWWNGSEQ ID NO: 1577 CGLFAELAELLWEGLENLIDWWNS SEQ ID NO: 1578CGLFAELAELLEEGLENLIDWWNS SEQ ID NO: 1579 CGLFAELAELLWEGLENLIDWWNQSEQ ID NO: 1580 CGLFAELAELLEEGLENLIDWWNQ SEQ ID NO: 1581CGLFAELAELLWEGLENLIDWWNE SEQ ID NO: 1582 CGLFAELAELLEEGLENLIDWWNESEQ ID NO: 1583 CELFEELAELLWEGLENLIDWWNQ SEQ ID NO: 1584CELFEELAELLWEGLENLIDWWNE SEQ ID NO: 1585 CELFEELAELLEEGLENLIDWWNGSEQ ID NO: 1586 CELFAELAELLWEGLENLIDWWNG SEQ ID NO: 1587CELFAELAELLEEGLENLIDWWNG SEQ ID NO: 1588 CELFAELAELLWEGLENLIDWWNSSEQ ID NO: 1589 CELFAELAELLEEGLENLIDWWNS SEQ ID NO: 1590CELFAELAELLWEGLENLIDWWNQ SEQ ID NO: 1591 CELFAELAELLEEGLENLIDWWNQSEQ ID NO: 1592 CELFAELAELLWEGLENLIDWWNE SEQ ID NO: 1593CELFAELAELLEEGLENLIDWWNE SEQ ID NO: 1594 CELFEELAELLWEGLHNLIDWWNGSEQ ID NO: 1595 CELFEELAELLWEGLHNLIDWWNS SEQ ID NO: 1596CELFEELAELLWEGLHNLIDWWNQ SEQ ID NO: 1597 CELFEELAELLWEGLHNLIDWWNESEQ ID NO: 1598 CELFGELEGFIENGLENLIDWWNG SEQ ID NO: 1599CGLFEELEGFIENGLENLIDWWNG SEQ ID NO: 1600 CGLFAELAGFIENGLENLIDWWNGSEQ ID NO: 1601 CGLFAELEGFIENGLENLIDWWNG SEQ ID NO: 1602CGLFGELAGFIENGLENLIDWWNG SEQ ID NO: 1603 CELFEELEGFIENGLENLIDWWNGSEQ ID NO: 1604 CELFAELAGFIENGLENLIDWWNG SEQ ID NO: 1605CGLFGELEGFIWNGLENLIDWWNG SEQ ID NO: 1606 CGLFGELEGFIENGLENLIDWWNGSEQ ID NO: 1607 CGLFGELEGFIENGLENLIDWWNQ SEQ ID NO: 1608CGLFGELEGFIENGLENLIDWWNE SEQ ID NO: 1609 CELFEELEGFIENGLENLIDWWNESEQ ID NO: 1610 CGLLEEIAELLEEGLENLIDWWNS SEQ ID NO: 1611CGLLEEIEELLWEGLENLIDWWNS SEQ ID NO: 1612 CELLEEIEELLEEGLENLIDWWNSSEQ ID NO: 1613 CGLLEEIAELLWEGLENLIDWWNS SEQ ID NO: 1614CELLEEIAELLWEGLENLIDWWNS SEQ ID NO: 1615 CELLEEIEELLEEGLENLIDWWNESEQ ID NO: 1616 CGLLEELEELLEEGLENLIDWWNS SEQ ID NO: 1617CGLLEELEELLEEGLENLLEWWNS SEQ ID NO: 1618 CGLLEEIAELLEEGLENLIDWWNGSEQ ID NO: 1619 CGLLAEIAELLEEGLENLIDWWNS SEQ ID NO: 1620CGLLAEIAELLWEGLENLIDWWNS SEQ ID NO: 1621 CGLLEEIEGFIENGLENLIDWWNSSEQ ID NO: 1622 CGLLEEIEGFIENGLENLIDWWNG SEQ ID NO: 1623CGLLEEIEELLEEGLE-Cit-LIDWWNS SEQ ID NO: 1624 CGLLEEIEELLEQGLENLIDWWNSSEQ ID NO: 1625 CGLLAELAELLEEGLENLIDWWNS SEQ ID NO: 1626CGLLEEIEELLEEGLENLIDWWNA SEQ ID NO: 1627 CGLL-Aib-EIEELLEEGLENLIDWWNSSEQ ID NO: 1628 CGLLEEIEELLEEGLENLIDWWN-Aib SEQ ID NO: 1629CGLLEEIEELLEE-Aib-LENLIDWWNG SEQ ID NO: 1630 CGLFGHIHHLIHHGLHNLIDWWNGSEQ ID NO: 1631 CGLFGEIHHLIHHGLHNLIDWWNG SEQ ID NO: 1632CGLFGEIHHLIHHGLENLIDWWNG SEQ ID NO: 1633 CGLFGEIHELIHHGLENLIDWWNGSEQ ID NO: 1634 CELLEEIEELLEEGLENLIDWWNS SEQ ID NO: 1635CGLFGELEELIEEGLENLIDWWNG SEQ ID NO: 1636 CGLLAEIEELLWEGLENLIDWWNSSEQ ID NO: 1637 CGLLEEIEELLEEGLENLLEWWNS SEQ ID NO: 1638C(b-ALA)LLEEIEELLEEGLENLIDWWNS SEQ ID NO: 1639 CGLLEEIEELLEEGLENLIDLWNSSEQ ID NO: 1640 CGLLEEIEELLEWGLENLIDWWNS SEQ ID NO: 1641CGLFGEIEELIEEGLENLIDWGNG SEQ ID NO: 1642 CGFFGEIAELIEEGLKNLIDWGNGSEQ ID NO: 1643 CGLFGEIEELIEEGLENLIDWANG SEQ ID NO: 1644CGLFGEIEELIEEGLENLIDWSNG SEQ ID NO: 1645 CGLFGEIEELIEEGLENLIDW-(Aib)-NGSEQ ID NO: 1646 CGLFGEIEELIEEGLENLIDWPNG SEQ ID NO: 1647CGLFGEIEELIEEGLENLIDWHNG SEQ ID NO: 1648 CGLFGEIEELIEEGLENLIDWQNGSEQ ID NO: 1649 CGLFGEIEELIEEGLENLIDWENG SEQ ID NO: 1650CGLFEEIAELIEEGLENLIDWGNG SEQ ID NO: 1651 CELFEELAELLWEGLENLIDWGNSSEQ ID NO: 1652 CGLFGEIAELIWEGLENLIDWGNG SEQ ID NO: 1653CGLLEEIEELLEEGLENLIDWGNS SEQ ID NO: 1654 CGLFAEIEELLEEGLENLIDWGNGSEQ ID NO: 1655 CGLL-(Aib)-EIEELLEEGLENLIDWWNS SEQ ID NO: 1656CGLFGEIEELIEEGLENLIDWNNG SEQ ID NO: 1657 CGLFGEIEELIEEGLENLIDWDNGSEQ ID NO: 1658 CGLFGEIEELIEEGLENLIDWONG SEQ ID NO: 1659CGLFAEIEELLEEGLENLIDWGNG SEQ ID NO: 1660 CGLL-Aib-EIEELLEEGLENLIDWGNSSEQ ID NO: 1661 CGLFGEIEELIEEGLENLIDGWNG SEQ ID NO: 1662CGLFGEIEELIEEGLENLIDLWNG SEQ ID NO: 1663 CGWFGEIEELIEEGLENLIDWWNGSEQ ID NO: 1664 CGLFGEVEELIEEGLENLIDWWNG SEQ ID NO: 1665CGLFGEIEEVIEEGLENLIDWWNG SEQ ID NO: 1666 CGLFGEIEELVEEGLENLIDWWNGSEQ ID NO: 1667 CGLFGEIEELAEEGLENLIDWWNG SEQ ID NO: 1668CGLFGEIEELIDEGLENLIDWWNG SEQ ID NO: 1669 CGLFGEIEELIEDGLENLIDWWNGSEQ ID NO: 1670 CGLFGEIEELIEEGLEALIDWWNG SEQ ID NO: 1671CGLFGEIEELIEEGLENIIDWWNG SEQ ID NO: 1672 CGLFGEIEELIEEGLEN-(Nle)-IDWWNGSEQ ID NO: 1673 CGLFGEIEELIEEGLENLIGWWNG SEQ ID NO: 1674CGLFGEIEELIEEGLENLIDAWNG SEQ ID NO: 1675 CGLLEEIEELLEEGLENLIDWWNESEQ ID NO: 1676 CELFEELAELLWEGLENLIDWWNE SEQ ID NO: 1677CGLFGEIEELIEEGLENLIGWWNG SEQ ID NO: 1678CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRR all (D) SEQ ID NO: 1679CGLFEAIEGFIENGWEGMIDGWYG all (D) SEQ ID NO: 1680CGLFGEIEELIENGLKNLIDWWYGYGRKKRRQRR all (D) SEQ ID NO: 1681CGLFEALLELLESLWELLLEAYGRKKRRQRR all (D) SEQ ID NO: 1682CGLFEEIEGFIENGWEGLIDWWYGYGHKKHHQHR all (D) SEQ ID NO: 1683CGLFGEIEELIEEGLENLIDWWNE all (D) SEQ ID NO: 1684CGLFGEIEELIEEGLENLIDWWNS all (D) SEQ ID NO: 1685CGLFGEIEELIEEGLENLIDWWNQ all (D) SEQ ID NO: 1686CYGRKKRRQRRLIRLWSHLIHIWFQNRRLKWKKK SEQ ID NO: 1687CGLFEAIEEFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 1688CGLFFAIEGFIENGWEGMIDWWYGYGRKKRRQRR ALL (D) SEQ ID NO: 1689CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRK(STEARYL) ALL (D) SEQ ID NO: 1690(STEARYL)GLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRC ALL (D) SEQ ID NO: 1691CFFGAIWEFIKSILK(STEARYL) ALL (D) SEQ ID NO: 1692CGIFEAIAGLLKNIFKGIFEAIAGLLKNIFK ALL (D) SEQ ID NO: 1693CIFGAIAGFIKNILKGLIDG ALL (D) SEQ ID NO: 1694CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(STEARYL) ALL(D) SEQ ID NO: 1695(LAURYL)FFGAIWEFIKSILC ALL (D) SEQ ID NO: 1696

The D-amino acid, retro-inverso, and cysteine conjugation point variantsof the peptides shown in Table 3 are also suitable.

The preferred peptides are listed in Table 4 below:

TABLE 4 Peptide Listing and ID Sequence SEQ IDCGLFEAIEGFIENGWEGMIDGWYGYGHKKHHQHH SEQ ID NO: 2C-bAla-LFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 3CGLFEAIEGFIEWGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 5CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQR SEQ ID NO: 7CGLFHALLHLLHSLWHGLLHAWYGYGHKKHHQHR SEQ ID NO: 11CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 13CGLFEAIEGFIENGWEG-Nle-IDGWYGYGRKKRRQRR SEQ ID NO: 19CGLLEALEGLLESLWEGLLEAWYGYGRKKRRQRR SEQ ID NO: 22CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(stearyl) SEQ ID NO: 27CGLFEAIAGFIEGGWPGLINGWYGYGRKKRRQRRLHLLHHLLHHLHHL SEQ ID NO: 28LHHLLHLLHHLLHHL CGLFEAIEGFIENGWEGMIDGWYGGGGLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 29 LHHLLHHL CGLFEAIEGFIENGWEGMIDGWYGLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 30 CGLFEALLELLESLWELLLEAYGRKKRRQRR SEQ ID NO: 31CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR SEQ ID NO: 32CGLFHALLHLLHSLWHLLLHAWYGYGRKKRRQRR SEQ ID NO: 55CGLFHALLHLLHSLWHLLLHAWYGYGHKKHHQHR SEQ ID NO: 56 CGIFGAIAGLLKNIFKSEQ ID NO: 63 CIFGAIAGFIKNIWKGLIDW SEQ ID NO: 64stearyl-WEAALAEALAEALAEHLAEALAEALEALAAYGRKKRRQRRC SEQ ID NO: 69CGFFHAFFHFFHSFWHGFFEA SEQ ID NO: 71 CGNFGEIEELIEEGLENLIDWWNGSEQ ID NO: 72 CFFGAIWEFIRNILEGF SEQ ID NO: 73 CFFGAIWEFIHSILSEQ ID NO: 74 CGLFGEIEEFIENGWKGLIDWWYG SEQ ID NO: 86CIFGIDDLIIGLLFVAIVEAGIGGYLLGSYGRKKRRQRR SEQ ID NO: 90 CFFGAIWEFIRSILKSEQ ID NO: 94 CFFGAIWEFIRSILE SEQ ID NO: 95CGLFEAIEGFIENGWEGMIDWWYGYGRKKRRQRR SEQ ID NO: 106CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR all (D) SEQ ID NO: 137CRRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLG SEQ ID NO: 192RRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLGC all(D) SEQ ID NO: 200CRRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLG all(D) SEQ ID NO: 201CGLFEAIEGFIENGWKGMIDGWYGYGRKKRRQRR SEQ ID NO: 228CGLFEAIEGFIENGWKGMIDGWYGYGRKKRRQRR SEQ ID NO: 228CGLFEAIEGFIENGWKGLIDWWYGYGRKKRRQRR SEQ ID NO: 266 CIFGAIAGFIKNIWSEQ ID NO: 283 CFFGAIWEFIRNIL SEQ ID NO: 333 FFGAIWEFIKSILCSEQ ID NO: 409 CFFGKIWEFIKSIL SEQ ID NO: 407 CFFGAIWEFAKSILSEQ ID NO: 423 CGLFHALLHLLHSLWHLLLEA SEQ ID NO: 436CGLFHALLHLLHSLWKLLLEW SEQ ID NO: 437 CGFFGEIAELIEEGLKGLIDWWNGSEQ ID NO: 461 CGLFGEIEELIEEGLENLIDWWNG SEQ ID NO: 462CFFGAIWEFIHSIL all (D) SEQ ID NO: 463 CGIFEAIAGLLKSILKK(stearyl)SEQ ID NO: 468 CGIFGAIAGLLKSILKK(stearyl) SEQ ID NO: 469CIFGAIAGFIKNILKGL all (D) SEQ ID NO: 470 CIFGAIAGFIKNILKGLK(stearyl)SEQ ID NO: 473 GLGKLINKIFGAIAGFIC all (D) SEQ ID NO: 474CGLFGEIEELIEEGLENLIDWWNG all(D) SEQ ID NO: 491CGNFGEIEELIEEGLENLIDWWNG all(D) SEQ ID NO: 492CGFFGEIAELIEEGLKGLIDWWNG all(D) SEQ ID NO: 493 CGIFEAIAGLLKNIF all(D)SEQ ID NO: 612 CIFGAIAGFIKNIWEGLI all (D) SEQ ID NO: 489CGLFGEIEELIEEGLENLIDWGNG all (D) SEQ ID NO: 1074CGLFGEIEELIEEGLENLIDWGNG SEQ ID NO: 1642CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRR all (D) SEQ ID NO: 1679CGLFEAIEGFIENGWEGMIDGWYG all (D) SEQ ID NO: 1680CGLFGEIEELIENGLKNLIDWWYGYGRKKRRQRR all (D) SEQ ID NO: 1681CGLFEALLELLESLWELLLEAYGRKKRRQRR all (D) SEQ ID NO: 1682CGLFEEIEGFIENGWEGLIDWWYGYGHKKHHQHR all (D) SEQ ID NO: 1683CGLFGEIEELIEEGLENLIDWWNE all (D) SEQ ID NO: 1684CGLFGEIEELIEEGLENLIDWWNS all (D) SEQ ID NO: 1685CGLFGEIEELIEEGLENLIDWWNQ all (D) SEQ ID NO: 1686 GFFGAIWEFIKSILCSEQ ID NO: 337

The D-amino acid, retro-inverso, and cysteine conjugation point variantsof the peptides shown in Table 4 are also preferred.

Targeting Ligands

The modular compositions of the present invention may comprise atargeting ligand. In some embodiments, this targeting ligand may directthe modular composition to a particular cell. For example, the targetingligand may specifically or non-specifically bind with a molecule on thesurface of a target cell. The targeting moiety can be a molecule with aspecific affinity for a target cell. Targeting moieties can includeantibodies directed against a protein found on the surface of a targetcell, or the ligand or a receptor-binding portion of a ligand for amolecule found on the surface of a target cell. Examples and a furtherdescription of targeting ligands can be found in WO2009/126933, which ishereby incorporated by reference.

The targeting ligands are selected from the group consisting of anantibody, a ligand-binding portion of a receptor, a ligand for areceptor, an aptamer, D-galactose, N-acetyl-D-galactose (GalNAc),multivalent N-acytyl-D-galactose, D-mannose, cholesterol, a fatty acid,a lipoprotein, folate, thyrotropin, melanotropin, surfactant protein A,mucin, carbohydrate, multivalent lactose, multivalent galactose,N-acetyl-galactosamine, N-acetyl-glucosamine, multivalent mannose,multivalent fructose, glycosylated polyaminoacids, transferin,bisphosphonate, polyglutamate, polyaspartate, a lipophilic moiety thatenhances plasma protein binding, a steroid, bile acid, vitamin B12,biotin, an RGD peptide, an RGD peptide mimic, ibuprofen, naproxen,aspirin, folate, and analogs and derivatives thereof.

The preferred targeting ligands are selected from the group consistingof D-galactose, N-acetyl-D-galactose (GalNAc), GalNAc2, and GalNAc3,cholesterol, folate, and analogs and derivatives thereof.

Lipids

Lipophilic moieties, such as cholesterol or fatty acids, when attachedto highly hydrophilic molecules such as nucleic acids can substantiallyenhance plasma protein binding and consequently circulation half life.In addition, lipophilic groups can increase cellular uptake. Forexample, lipids can bind to certain plasma proteins, such aslipoproteins, which have consequently been shown to increase uptake inspecific tissues expressing the corresponding lipoprotein receptors(e.g., LDL-receptor or the scavenger receptor SR-B1). Lipophilicconjugates can also be considered as a targeted delivery approach andtheir intracellular trafficking could potentially be further improved bythe combination with endosomolytic agents.

Exemplary lipophilic moieties that enhance plasma protein bindinginclude, but are not limited to, sterols, cholesterol, fatty acids,cholic acid, lithocholic acid, dialkylglycerides, diacylglyceride,phospholipids, sphingolipids, adamantane acetic acid, 1-pyrene butyricacid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexylgroup, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecylgroup, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid,O3-(oleoyl)cholenic acid, dimethoxytrityl, phenoxazine, aspirin,naproxen, ibuprofen, vitamin E and biotin etc. Examples and a furtherdescription of lipids can be found in WO2009/126933, which is herebyincorporated by reference.

The preferred lipid is cholesterol.

Solubilizing Agents

The modular composition may comprise one or more other moieties/ligandsthat may enhance aqueous solubility, circulation half life and/orcellular uptake. These can include naturally occurring substances, suchas a protein (e.g., human serum albumin (HSA), low-density lipoprotein(LDL), high-density lipoprotein (HDL), or globulin); or a carbohydrate(e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin orhyaluronic acid). These moieties may also be a recombinant or syntheticmolecule, such as a synthetic polymer or synthetic polyamino acids.Examples include polylysine (PLL), poly L-aspartic acid, poly L-glutamicacid, styrene-maleic acid anhydride copolymer,poly(L-lactide-co-glycolied) copolymer, divinyl ether-maleic anhydridecopolymer, N-(2-hydroxypropyl)methacrylamide copolymer (HMPA),polyethylene glycol (PEG, e.g., PEG-0.5K, PEG-2K, PEG-5K, PEG-10K,PEG-12K, PEG-15K, PEG-20K, PEG-40K), methyl-PEG (mPEG), [mPEG]2,polyvinyl alcohol (PVA), polyurethane, poly(2 ethylacryllic acid),N-isopropylacrylamide polymers, or polyphosphazine. Examples and afurther description of solubilizing agents can be found inWO2009/126933, which is hereby incorporated by reference.

The preferred solubilizing group is PEG 0.5K to 30K.

Method of Treatment

In one aspect, the invention features, a method of treating a subject atrisk for or afflicted with a disease that may benefit from theadministration of the modular composition of the invention. The methodcomprises administering the modular composition of the invention to asubject in need thereof, thereby treating the subject. Theoligonucleotide that is administered will depend on the disease beingtreated. See WO2009/126933 for additional details regarding methods oftreatments for specific indications.

Formulation

There are numerous methods for preparing conjugates of oligonucleotidecompounds. The techniques should be familiar to those skilled in theart. A useful reference for such reactions is Bioconjugate Techniques,Hermanson, G. T., Academic Press, San Diego, Calif., 1996. Otherreferences include WO2005/041859; WO2008/036825 and WO2009/126933.

EXAMPLES

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The contents of allreferences, pending patent applications and published patents, citedthroughout this application are hereby expressly incorporated byreference. The siRNAs described herein were designed to target theubiquitously expressed gene SSB (Sjogren syndrome antigen B;NM_009278.4).

Linker groups may be connected to the oligonucleotide or siRNA strand(s)at a linkage attachment point (LAP) and may include anycarbon-containing moiety, in some embodiments having at least one oxygenatom, at least one phosphorous atom, and/or at least one nitrogen atom.In some embodiments, the phosphorous atom forms part of a terminalphosphate, or phosphorothioate, group on the linker group, which mayserve as a connection point for the oligonucleotide strand. In certainembodiments, the nitrogen atom forms part of a terminal ether, ester,amino or amido (NHC(O)—) group on the linker group, which may serve as aconnection point for the linkers of interest, endosomolytic unit, cellpenetrating peptide, solubilizing group, lipid, targeting group, oradditional linkers of interest. These terminal linker groups include,but are not limited to, a C₆ hexyl, C₅ secondary-hydroxy, C₃ thiol or C₆thiol moiety. An example from the RNA sequences described below is C6hexyl: [(CH₂)₆NH₂].

The siRNA sequences described in the Examples herein are shown in Table5.

TABLE 5 Sequence SEQ ID Entry Code Compound stand Seuqence NO:  1 bCTNNB1 passenger [6amiL][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG]1697 [fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluG][clickA][fluA][fluA][omeUs][omeU][iB][C3SH] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU] 1698[omeC][fluA][omeA][fluU][omeC][fluC][omeA][fluA][omeC][fluA][omeG][omeUs][omeU]  2 c ApoB passenger[C6SH][iB][omeC][omeU][omeU][omeU][fluA][fluA][omeC] 1699[fluA][fluA][omeU][omeU][omeC][omeC][omeU][fluG][fluA][fluA][fluA][omeU][dTs]dT[iB][6amiL] ApoB guide[rAs][rUs][rUs][omeU][omeC][fluA][fluG][fluG][fluA][fluA] 1700[omeU][omeU][fluG][fluU][omeU][fluA][fluA][fluA][fluG] [omeUs][omeU]  3d CTNNB1 passenger[6amiL][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG] 1701[fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluG][clickA][fluA][fluA][omeUs][omeU][iB][C3SH] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU][omeC] 1702[fluA][omeA][fluU][omeC][fluC][omeA][fluA][omeC][fluA][omeG][omeUs][omeU]  4 e CTNNB1 passenger[6amiL][iB][omeC][omeU][fluG][omeU][omeU][fluG][fluG] 1703[fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluG][clickA][fluA][fluA][omeUs][omeU][iB][C3SH] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU][omeC] 1704[fluA][omeA][fluU][omeC][fluC][omeA][fluA][omeC][fluA][omeG][omeUs][omeU]  5 f CTNNB1 passenger[6amiL][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG]  175[fluA][omeU][omeU][fluG][fluA][clickU][omeU][omeC][fluG][fluA][clickA][fluA][omeUs][omeU][iB][C3SHSup] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU][omeC] 1706[fluA][omeA][fluU][omeC][fluC][omeA][fluA][omeC][fluA][omeG][omeUs][omeU]  6 g CTNNB1 passenger[6amiL][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG] 1707[clickA][omeU][omeU][fluG][fluA][clickU][omeU][omeC][fluG][fluA][clickA][fluA][omeUs][omeU][iB][C3SHSup] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU][omeC] 1708[fluA][omeA][fluU][omeC][fluC][omeA][fluA][omeC][fluA][omeG][omeUs][omeU]  7 h CTNNB1 passenger[LiCholinker][iB][omeC][omeU][fluG][omeU][omeU][fluG] 1709[fluG][fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluG][fluA][fluA][fluA][omeUs][omeU][iB][6amiL] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU] 1710[omeC][fluA][omeA][fluU][omeC][fluC][omeA][fluA][omeC][fluA][omeG][omeUs][omeU]  8 i CTNNB1 passenger [amino modifier C2 1711dT][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG][fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluqG][clickA][fluA][fluA][omeUs][omeU][iB][C3SSC3OH] 1712 CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU][omeC][fluA][omeA][fluU][omeC][fluC][omeA][fluA][omeC][fluA][omeG][omeUs][omeU]  9 j CTNNB1 passenger[6amiL][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG] 1713[fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluG][fluA][fluA][fluA][omeUs][omeU][iB][C3SH] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU][omeC] 1714[clickA][omeA][fluU][omeC][fluC][clickA][fluA][omeC][fluA][omeG][omeUs][omeUSup] 10 k CTNNB1 passenger[6amiL][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG] 1715[fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluG][fluA][fluA][fluA][omeUs][omeU][iB][C3SH] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU][omeC] 1716[fluA][omeA][fluU][omeC][fluC][clickA][fluA][omeC][fluA][omeG][omeUs][omeU] 11 l CTNNB1 passenger[6amiL][iB][omeC][omeU][fluG][omeU][omeU][fluG][fluG] 1717[fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluG][fluA][fluA][fluA[omeUs][omeU][iB]6amiL] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU][omeC] 1718[fluA][omeA][fluU][omeC][fluC][clickA][fluA][omeC][fluA][omeG][omeUs][omeU] 12 m CTNNB1 passenger[6amiL][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG] 1719[fluA][omeU][omeU][fluG][fluA][clickU][omeU][omeC][fluG][fluA][clickA][fluA[]omeUs][omeU][iB][C3SHSup] CTNNB1 guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU][omeC] 1720[fluA][omeA][fluU][omeC][fluC][clickA][fluA][omeC][fluA][omeG][omeUs][omeU]As used herein, ome=2′ methoxy; flu=2′ fluoro; click=2′ propagyl;iB=inverted abasic; “s” subscript=phosphorothioate; and r=2′ ribo;6amil=n-hexylamino; C3 SH=n-propylthiol; and C6SH=n-hexylthiol.

Preparations of tetraGalNAc ligands and tetraGalNAc-siRNA conjugates aredescribed below in the examples and synthetic schemes. Note that thesiRNA depictions below are for illustrative purposes. Specific sequenceinformation can be found in Table 5.

Section A Examples 1-2 Synthesis of TetraGalNAc Ligand Compounds A9 andA10

The following Scheme 1 was used to prepare TetraGalNAc Compounds 9 and10.

Synthesis of (2S)-2,6-bis[bis (prop-2-yn-1-yl)amino]hexanoic acid(Compound A1)

Into a 2000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed a solution of(2S)-2,6-diaminohexanoic acid (50 g, 342.03 mmol, 1.00 equiv) inacetonitrile (1000 mL) and heated to 50° C. To this was added potassiumhydroxide (22.6 g, 0.4025 mol, 1.00 equiv, 85%). The resulting solutionwas stirred for 30 min. Then 3-bromoprop-1-yne (29.5 mL, 1.00 equiv) wasadded. The resulting solution was stirred for 1 hour at 50° C.additional potassium hydroxide (22.6 g, 0.4025 mol, 1.00 equiv) wasadded to the solution and stirred for 30 min at 50° C. To this was added3-bromoprop-1-yne (29.5 mL, 1.00 equiv). The resulting solution wasstirred for 1 hour. To this was added potassium hydroxide (22.6 g,0.4025 mol, 1.00 equiv) again. The resulting solution was stirred for 30min at 50° C., followed by addition of more 3-bromoprop-1-yne (29.5 mL,1.00 equiv). The resulting solution was stirred for 1 hour. To this wasadded potassium hydroxide (22.6 g, 0.4025 mol, 1.00 equiv). Theresulting solution was stirred for 30 min. To this was added3-bromoprop-1-yne (29.5 mL, 1.00 equiv). The resulting solution wasstirred for 3 hours. The reaction mixture was cooled to 25° C. with awater/ice bath. The solid was filtered out. The filtrate was adjusted topH 4 with HCl (6M). The solid was filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with dichloromethane/methanol (100:1-25:1). Thisresulted in (2S)-2,6-bis[bis (prop-2-yn-1-yl)amino]hexanoic acid(Compound A1) as a light yellow oil.

MS(ES, m z): 297.2, [M−H]⁻¹HNMR(CDCl₃, 500 MHz, ppm): 3.62 (d, J=2.0 Hz,4H), 3.52-3.49 (m, 1H), 3.50 (d, J=2.4 Hz, 4H), 2.62 (t, J=7.1 Hz, 2H),2.30 (t, J=2.4 Hz, 2H), 2.27 (t, J=2.4 Hz, 2H), 1.88-1.79 (m, 2H),1.60-1.53 (m, 2H), 1.52-1.43 (m, 2H).

Synthesis of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (CompoundA3)

Into a 2000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed a solution of2-(2-hydroxyethoxy)ethan-1-ol (A2, 42.4 g, 399.55 mmol, 1.00 equiv) indichloromethane (1000 mL) and triethylamine (27.9 g, 275.72 mmol, 0.25equiv). To the above was added p-toluenesulfonyl chloride (19.1 g,100.18 mmol, 0.50 equiv). After stirred for 1 h at 25° C., the resultingmixture was washed with 1×500 mL of aq. potassium hydrosulfate (1M) and1×500 mL of aq. sodium bicarbonate (5%) respectively. The organic layerwas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column and eluted withdichloromethane/methanol (100:1). This resulted in2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (Compound A3) as acolorless oil.

Synthesis of 2-(2-azidoethoxy)ethan-1-ol (Compound A4)

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of2-(2-[[(4-2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (A3, 50 g,192.08 mmol, 1.00 equiv) in N,N-dimethylformamide (250 mL). This wasfollowed by the addition of sodium azide (18.79 g, 289.03 mmol, 1.50equiv) at 25° C. The resulting solution was stirred for 5 h at 100° C.in an oil bath. The reaction mixture was cooled and filtered. Thefiltrate was concentrated under vacuum. The residual solution wasdiluted with 1000 mL of dichloromethane and washed with 1×500 mL ofwater. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with dichloromethane/methanol (80:1). This resulted in2-(2-azidoethoxy)ethan-1-ol (Compound A4) as a colorless oil.

¹HNMR (CDCl₃, 400 MHz, ppm): 3.42-3.45 (t, J=4.8 Hz, 2H), 3.63-3.65 (t,J=4.8 Hz, 2H), 3.71-3.74 (t, J=4.8 Hz, 2H), 3.71-3.79 (m, 2H).

Synthesis of(3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyltriacetate (Compound A6)

Into a 2000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed a solution of(3R,4R,5R,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triolhydrochloride (A5, 120 g, 556.50 mmol, 1.00 equiv) in pyridine (1200mL). This was followed by the addition of acetic anhydride (341.6 g,3.35 mol, 6.00 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred overnight at 25° C. The reaction was then quenchedby the addition of 8000 mL of water/ice. The solid was collected byfiltration. This resulted in(3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyltriacetate (Compound A6) as a white solid.

Synthesis of(3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyldiacetate (Compound A7)

Into a 2000-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of(3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyltriacetate (A6, 30 g, 77.05 mmol, 1.00 equiv) in dichloromethane (1500mL), then added iron (III) chloride (30 g, 184.95 mmol, 2.40 equiv). Theresulting mixture was stirred for 2 h at 25° C. The reaction was thenquenched by the addition of 1000 mL of water/ice. The organic layer waswashed with 1×1000 mL of sodium aq. bicarbonate and 1×1000 mL of water,dried over anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in(3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyldiacetate (Compound A7) as yellow oil. ¹HNMR(CDCl₃, 300 MHz, ppm): 2.03(s, 9H), 2.12 (s, 3H), 3.97-4.27 (m, 4H), 4.90-4.93 (m, J=3.3 Hz, 1H),5.45-5.47 (t, J=3.0 Hz, 1H), 5.98-6.00 (d, J=6.6 Hz, 1H).

Synthesis of(2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-[2-(2-azidoethoxy)ethoxy]tetrahydro-2H-pyran-3,4-diyldiacetate (Compound A8)

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of(3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyldiacetate (A7, 40 g, 121.47 mmol, 1.00 equiv) in 1,2-dichloroethane (200mL), 2-(2-azidoethoxy)ethan-1-ol (A4, 23.89 g, 182.18 mmol, 1.50 equiv).To the above several 4A zeolite was added. The resulting mixture wasstirred for 1 h at 25° C. Then trimethylsilyl trifluoromethanesulfonate(10.8 mL, 0.50 equiv) was added. After stirred overnight at 25° C., thereaction mixture was diluted with 500 mL of dichloromethane and washedwith 1×500 mL of water, 1×500 mL of aq. sodium bicarbonate and 1×500 mLof water. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with dichloromethane/methanol (100:1). This resultedin(2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-[2-(2-azidoethoxy)ethoxy]tetrahydro-2H-pyran-3,4-diyldiacetate (A8) as a colorless oil.

MS(m/z): 461.1, [M+H]⁺

¹HNMR(CDCl₃, 500 MHz, ppm) 5.78 (d, J=8.90 Hz, 1H), 5.36 (d, J=2.9 Hz,1H), 5.22 (dd, J=11.2, 3.6 Hz, 1H), 4.77 (d, J=8.3 Hz, 1H), 4.19-4.12(m, 2H), 4.11-4.05 (m, 1H), 3.98-3.92 (m, 2H), 3.82-3.78 (m, 1H),3.71-3.63 (m, 4H), 3.49-3.38 (m, 2H), 2.16 (s, 3H), 2.05 (s, 3H), 2.01(s, 3H), 1.97 (s, 3H).

Synthesis of(S)-2,6-bis(bis((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)hexanoicacid (Compound A9, tetraGalNAc Acetate) (A9) (Ex. 1)

Into a 250-mL round bottom flask purged and maintained with an inertatmosphere of nitrogen was charged (2S)-2,6-bis [bis (prop-2-yn-1-yl)amino]hexanoic acid (A1, 1.0 g, 1.0 equiv),(2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-[2-(2-azidoethoxy)ethoxy]tetrahydro-2H-pyran-3,4-diyldiacetate (A8, 9.26 g, 6.0 equiv), anhydrous THF 50 mL, CuBr.SMe₂ (0.138g, 0.20 equiv), and anhydrous DBU (1.5 ml, 3.0 equiv) in respectiveorder. The resulting solution was stirred for 16 h at room temperature,quenched with acetic acid (0.75 mL, 4.0 equiv), treated with MP-TMTresin (Part No: 801472, from Biotage) (9 g), aged at room temperaturefor 16 h, filtered, and concentrated the filtrate to a foam solid. Thesolid was then dissolved in CH₂Cl₂ (140 mL), and washed with AcOH/NaClsolution (140 mL). The AcOH/NaCl solution was prepared with 1 mL AcOHand 100 mL 20% NaCl solution. The bottom organic layer was concentrated,and purified on a SiO₂ column (220 g), eluting with CH₂Cl₂/MeOH. Thisresulted in(S)-2,6-bis(bis((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)hexanoicacid (Compound A9) as a white solid.

MS(m z): 2139.5, [M+H]⁺

Synthesis of(S)-2,6-bis(bis((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)hexanoicacid (Compound A10, TetraGalNAc) (A10) (Ex. 2)

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was charged(S)-2,6-bis(bis((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)hexanoicacid (A9, 6.9 g, 1.0 equiv), Na₂CO₃ (6.83 g, 20 eq), water (56 mL), andMeOH (32 mL) in respective order. The reaction was aged at roomtemperature for 16 h, concentrated to residue, redissolved in water (50mL), and purified on Combiflash C18 gold reverse column (415 g), elutingwith water/MeCN. After concentration under vacuum, the product wasdissolved in minimum amount of water, and lyophilized to obtain(S)-2,6-bis(bis((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)hexanoicacid (Compound A10) as a white solid.

MS(m z): 1657 [M+Na]⁺

¹HNMR(D₂O, 500 MHz, ppm): 8.05 (s, 2H), 7.91 (s, 2H), 4.62 (t, J 5.0 Hz,4H), 4.57 (t, J=5.0 Hz, 4H), 4.45-4.41 (d, J=8.6 Hz, 4H), 3.99-3.82 (m,28H), 3.80-3.61 (m, 28H), 3.14 (t, J=7.1 Hz, 1H), 2.52 (broad s, 2H),1.99 (s, 6H), 1.98 (s, 6H), 1.73 (m, 2H), 1.60 (m, 2H), 1.29 (m, 2H).

Section B Preparation of B2 to B5 Examples 3-6

Scheme 2 as shown in FIG. 5A-1 to FIG. 5D, was used to prepare BConjugates (Ex. 3-6).

Synthesis of B2 (Ex. 3)

A10 (86 mg, 0.053 mmol) and DIEA (57.6 μL, 0.330 mmol) were dissolved inDMSO (500 μL), then added to a solution of HATU (301 μL, 0.079 mmol) andstirred for 15 min. Starting material passenger strand B1 (101 mg, 0.013mmol) was dissolved in water (168 μL) and DMSO (1.5 mL). The HATUsolution was added to the RNA solution and aged for 15 min. The reactionmixture was diluted with water (50 mL) and centrifugal dialyzed threetimes against water over a 3 k membrane. The concentrate was loaded ontoan HPLC fitted with a Dionix ProPac SAX 22×250 mm column. The productwas gradient eluted starting at 95% A (2:3 H₂O:2,2,2-trifluoroethanol,20 mM TEA) up to 40% solvent B (2:3 H₂O:2,2,2-trifluoroethanol, 20 mMTEA, 1M CsCl). The fractions were diluted with water to reduce the2,2,2-trifluoroethanol content to 25% and centrifugal dialyzed threetimes against water over a 3 k membrane. The concentrate was freezedried to afford the product as a white amorphous solid. Expected mass:9267.5, found mass: 9267.0

Synthesis of B3 (Ex. 4)

To a solution of B2 (606 mg, 0.065 mmol) in water (32 mL) was added TEAA(1.64 mL, 2M), aqueous DTT (0.65 mL, 1M), and TEA (0.65 mL, 4.69 mmol).The reaction mixture was aged for 10 min. The reaction mixture was thendiluted with water and centrifugal dialyzed three times against waterover a 3 k membrane. The concentrate was taken forward without furtherisolation. Expected mass: 9177.4, found mass: 9179.0

Synthesis of B4 (Ex. 5)

To a solution of B3 (350 mg, 0.038 mmol) in water (3 mL) was addedN-(2-aminoethyl)-maleimide trifluoroacetate salt (194 mg, 0.763 mmol).The reaction mixture was aged for 30 min, after which it was purified byRP-HPLC (95:5-5:95% A:B linear gradient (A=100 mM aqueous TEAA; B=100 mMTEAA in acetonitrile) Waters Phenyl xbridge Column. Fractions containingB4 were centrifugal dialyzed three times against water over a 3 kmembrane and the concentrate was lyophilized to give product as a whiteamorphous solid.

Synthesis of B5 (Ex. 6)

To a solution of B4 (286 mg, 0.031 mmol) in aqueous sodium bicarbonate(3.0 mL, 200 mM) was added a solution of NHS-dPEG12-SPDP (280 mg, 0.307mmol) in acetonitrile (0.5 mL). The reaction mixture was aged for 30min, after which it was treated with aqueous TEAA (1.0 mL, 2M) andpurified by RP-HPLC (95:5-5:95% A:B linear gradient (A=100 mM aqueousTEAA; B=100 mM TEAA in acetonitrile) Waters Phenyl xbridge Column.Fractions containing B5 were centrifugal dialyzed three times againstwater over a 3K membrane and the concentrate was lyophilized to giveproduct as a white amorphous solid. Measured mass=10117

Examples 7-8

Preparation of B6-seq32

Scheme 3 as shown in FIG. 6A to FIG. 6B was used to prepare ConjugatesB6-P32 and B8-seq32 (Ex. 7-8).

Synthesis of Conjugate B6-seq32 (Ex. 7)

B5 (50 mg, 5 umol, 1 eq.) was dissolved in 50 mM AcOH in2,2,2-trifluoroethanol (5 mL). Peptide Seq32 (51 mg, 13 umol, 2.5 eq.)was dissolved in guanidine-HCl (8M, 500 uL), diluted with 50 mM AcOH in2,2,2-trifluoroethanol (5 mL). The peptide solution was added dropwiseto the stirring RNA solution over 5 min, and the reaction was left atroom temperature for 1 hour. The reaction was diluted with formamide (10mL), and 1.5 mL aliquots of the reaction mixture were loaded onto anHPLC fitted with a Dionex ProPac SAX-10 22×250 mm column. The productwas gradient eluted starting at 98% solvent A (2:3H₂O:2,2,2-trifluoroethanol, 40 mM TEA) up to 35% solvent B (2:3H₂O:2,2,2-trifluoroethanol, 40 mM TEA, 1M guanidine-HCl) over 10 min at20 mL/min. The fractions were diluted with water to reduce the2,2,2-trifluoroethanol content to 25% and centrifugal dialyzed threetimes against water over a 10 k membrane. The concentrate was freezedried to afford the product as a white amorphous solid. Expected mass:13961.9, found mass: 13962.0

Synthesis of Conjugate B8-seq32-b (Ex. 8)

Guide strand (B7, 17.7 mg) was dissolved in water (5 mL) and added to avial containing B6-seq 42 (36.2 mg). The solution was thoroughly mixedand left at room temperature for 2 hours. The solution was freeze driedto afford the duplex as a white amorphous solid.

Synthesis of Additional B8-Peptide Conjugates

Additional conjugates of B8 and Peptide Sequence and duplexes wereprepared in a manner analogous to that used for B8-seq32-b.

Examples 9-11

Preparation of B9 and B10-seq32 and 11-seq32

Scheme 4 as shown in FIG. 7A, FIG. 7B and FIG. 7C was used to prepareB9, B10-seq32 and B11-seq32.

Synthesis of B9 (Ex. 9)

Compound B3 (120 mg, 0.0132 mmol) in water (5 mL) was added dropwise toa stirring solution of 2,2′-dipyridyldisulfide (29 mg, 0.132 mmol, 10eq.) dissolved in methanol (5 mL). The solution was diluted with waterto bring the methanol content to 20% and centrifugal dialyzed threetimes against water over a 3K membrane. The concentrate was freeze driedto afford the product as an amorphous white solid. Expected mass:9166.5, found mass: 9165.5

Synthesis of B10-seq32 (Ex. 10)

B9 (15 mg, 1.615 umol) was dissolved in water (150 uL) and was dilutedwith 50 mM AcOH in TFE (1.5 mL). In a separate vial, P32 (8.79 mg, 2.155umol) was dissolved in 8 M guanidine HCl (60 uL) and diluted with 50 mMAcOH in TFE (1.5 mL), then added to the RNA solution. The reactionmixture was aged for 15 min, then was diluted with formamide andpurified by AEX (95:5-55:45 A:B linear gradient (A=20 mM TEA in 60%aqueous TFE; B=1M CsCl and 20 mM TEA in 60% aqueous TFE), Dionix Propaccolumn. Fractions containing B10-Seq 32 were centrifugal dialyzed threetimes against water over a 10K membrane and the concentrate waslyophilized to give product as a white amorphous solid.

Synthesis of B11-seq32-b (Ex. 11)

B10-seq 32 (9.68 mg, 0.730 umol) was treated with a solution of B7 (5.00mg, 0.730 umol) dissolved in PBS (500 uL) and aged for 30 min. Excessguide strand was removed by AEX purification (95:5-55:45 A:B lineargradient (A=20 mM TEA in 60% aqueous TFE; B=1M CsCl and 20 mM TEA in 60%aqueous TFE), Dionix Propac column. Fractions containing B11-seq 32 werecentrifugal dialyzed three times against water over a 10K membrane andthe concentrate was lyophilized to give product as a white amorphoussolid.

Examples 12-14 Additional Synthesis of B11-Peptide Conjugates.

Additional conjugates of B11 and peptide sequences and correspondingduplexes were prepared in a manner analogous to that used forB11-seq32-b.

Scheme 5 is shown in FIG. 7D, FIG. 7E and FIG. 7F.

Synthesis of B12 (Ex. 12):

B3 (50 mg, 5.4 μmol) was dissolved in water (3 mL, ˜17 mg/mL) andCompound 1,1,1′-(ethane-1,2-diyl)bis(1H-pyrrole-2,5-dione), (16 mg,0.073 mmol) was dissolved in DMF (1.2 mL) in separate vials. The B3solution was added to Compound 1 solution and stirred for 10 min. Thereaction was diluted with water to 15 mL and then dialyzed 4 times on 3K MWCO membrane against water. The reaction was then filtered (0.22 μmsyringe filter) and lyophilzed to afford a white solid, B12. Expectedmass: 9397.535. Observed mass: 9400.0.

Synthesis of B12-seq13 (Ex. 13): See Synthesis of B10-seq32 for reactionprocedure.

B12-seq13. Expected mass: 13518.215

Synthesis of B13-seq13-b (Ex. 14): See Synthesis of B11-seq32 forreaction procedure.

B13-seq13-b. Expected mass: 20370.215

Additional Synthesis of B13-Peptide Conjugates.

Additional conjugates of B13 and peptide sequences were prepared in amanner analogous to that used for B13-seq13.

Examples 15-16

Preparation of B15-seq32 and B16-seq32-b

Scheme 6 as shown in FIG. 7G-1 to FIG. 7G-2 was used to prepareB16-seq32 and B17-seq32-b.

Synthesis of B14

B3 (100 mg, 10.9 μmol) was dissolved in water (10 mL) and dioxane (20mL) was treated with bis maleimide dissolved in dioxane (3.8 mL) to givea cloudy mixture. The reaction was stirred for 1.5 hours, after which itwas quenched with N-methylmaleimide (36.3 mg, 0.327 mmol). The reactionmixture was diluted with water and centrifugal dialyzed once againstwater over a 3 k membrane. The concentrate was filtered and purified byRP-HPLC (95:5-5:95% A:B linear gradient (A=100 mM aqueous TEAA; B=100 mMTEAA in acetonitrile) Waters Phenyl xbridge Column). Fractionscontaining product were dialyzed and lyophilized to give B14 as anamorphous white powder. Measured mass=9531

Synthesis of B15-seq 32 (Ex. 15)

B14 (5 mg, 0.524 μmol) was dissolved in formamide solution (2M thiourea,50 mM MES buffer at pH 6.5, 500 μL). In a separate vial, peptidesequence 32 (4.28 mg, 1.048 μmol) was dissolved in formamide solution(2M thiourea, 50 mM MES buffer at pH 6.5, 500 μL), then was added to theRNA solution. After aging one hour at room temperature, the reactionmixture was loaded onto an HPLC fitted with a Dionex ProPac SAX-1022×250 mm column. The product was gradient eluted starting at 98%solvent A (2:3 H2O:2,2,2-trifluoroethanol, 40 mM TEA) up to 35% solventB (2:3 H2O:2,2,2-trifluoroethanol, 40 mM TEA, 1M guanidine-HCl) over 10min at 20 mL/min. The fractions were diluted with water to reduce the2,2,2-trifluoroethanol content to 25% and centrifugal dialyzed threetimes against water over a 10 k membrane. The concentrate was freezedried to afford the product as a white amorphous solid.

Synthesis of B16-seq32-b (Ex. 16)

B15-seq 32 (2.11 mg, 0.155 μmol) was treated with a solution of B7(1.062 mg, 0.155 μmol) in water (212 μL) and aged at room temperaturefor 2 hours. The solution was lyophilized to give the product as a whiteamorphous solid.

Section C Examples 17-21

Preparation of C1 to C3, C4-seq32 and C6-seq32

Scheme 7 as shown in FIG. 8A to FIG. 8D was used to prepare C1 to C3,C4-seq32 and C6-seq32.

Synthesis of C1 (Ex. 17)

1,2-Diaminododecane (100 mg, 0.499 mmol) was dissolved in chloroform(3.3 mL) and cooled to 0° C., then treated withN-methoxycarbonyl-maleimide (234 mg, 1.50 mmol) and tetrabutylammoniumhydrogen sulfate (170 mg, 0.499 mmol). DIPEA (209 uL, 1.20 mmol) wasslowly added and the reaction aged for 10 minutes at 0° C. The ice bathwas removed and the reaction was treated with aqueous saturated sodiumbicarbonate solution (6.6 mL). After aging 3.5 hours at roomtemperature, the reaction mixture was extracted with ethyl acetate (3×15mL). The combined organic layers were dried with sodium sulfate and thensolvent removed in vacuo. The crude product was purified by flashchromatography with a 100:0-0:100% A:B linear gradient (A=hexanes;B=ethyl acetate). Fractions containing product were pooled andconcentrated to give C1 as a fine white powder. ¹H NMR (CDCl₃):1.24-1.28 (m, 12H), 1.55-1.61 (m, 4H), 3.50 (t, 4H J=7.4 Hz), 6.68 (s,4H). Measured mass=361.

Synthesis of C2 (Ex. 18)

Step 1. 3′ Hamino 5′ C6 disulfide siRNA (46.9 mg, 6.16 μmol) wasdissolved in 9:1 DMSO/water (782 μl). TetraGalNAc (40.0 mg, 0.025 mmol)and DIEA (26.9 μl, 0.154 mmol) were dissolved in DMSO (200 μl), thenadded solution of HATU (14.0 mg, 0.037 mmol) in DMSO (141 μL) andstirred at RT for 15 minutes. This solution was added to the RNAsolution and aged for 30 minutes. The reaction was diluted with DI waterand dialyzed once to remove DMSO and purified by AEX (95:5-65:35 A:Blinear gradient (A=20 mM TEA in 60% aqueous TFE; B=1M CsCl and 20 mM TEAin 60% aqueous TFE), Dionix Propac column). Fractions containing productwere pooled, dialyzed, and lyophilized. Measured mass=9233.

Step 2. To this solid (30.8 mg, 3.34 μmol) was added TCEP (19.13 mg,0.067 mmol) and DI water (2 mL). The reaction was stirred at RT for 1hour, then aged overnight at 5° C. The reaction was diluted with DIwater and dialyzed twice against DI water to give a solution of C2 thatwas used in further reactions without isolation.

Synthesis of C3 (Ex. 19)

C2 (60.1 mg, 6.60 umol, prepared in a manner analogous to B3) dissolvedin DI water (37 mL) was treated with C1 (23.8 mg, 66.0 umol) dissolvedin DMF (7 mL) to give a cloudy solution. The reaction was agedovernight, at which point dioxane (18 mL) was added to solubilize thereaction mixture. After aging for 30 additional minutes, the reactionwas diluted with DI water. It was then dialyzed once against DI water,filtered, and purified by RP-HPLC (95:5-5:95% A:B linear gradient (A=100mM aqueous TEAA; B=100 mM TEAA in acetonitrile) Waters Phenyl xbridgeColumn). Fractions containing product were dialyzed and lyophilized togive C3 as an amorphous white powder. Measured mass=9458.

Synthesis of C4-seq32 (Ex. 20)

C3 (10 mg, 1.057 umol) was dissolved in formamide modified with 20 mMMES buffer and 2 M thiourea (1 mL) and was added to P32 (8.62 mg, 2.11umol). After 20 mins, LC-MS indicated good conversion to desiredproduct. Reaction was purified by AEX (95:5-55:45 A:B linear gradient(A=20 mM TEA in 60% aqueous TFE; B=1M CsCl and 20 mM TEA in 60% aqueousTFE), Dionix Propac column). Fractions containing product were dialyzedto give C4-P32.

Synthesis of C6-seq32-(Ex. 21)

C4 (6.78 mg, 0.501 μmol) dissolved in DI water (3.40 mL) was treatedwith guide strand C5 (3.44 mg, 0.501 μmol) dissolved in DI water (530μL). Analytical SAX indicated good duplex purity with some excess guidestrand observed. Solution was lyophilized to give C6 as an amorphouswhite powder. Measured mass=passenger strand: 13539, guide strand: 6869.

Additional Synthesis of C6-peptide Conjugates.

Additional conjugates of C6 and Peptide Sequence were prepared in amanner analogous to that used for C6-seq32-c.

Examples 22-27

Preparation of C7 to C10, C11-P32 and C12-seq32-a

Scheme 8 as shown in FIG. 9A to FIG. 9E was used to prepare C7 to C10,C11-seq32 and C12-seq32.

Synthesis of C7 (Ex. 22)

Icosanedioic acid (600 mg, 1.752 mmol) was suspended in toluene (11 mL)and treated with DIEA (673 μL, 3.85 mmol) and DPPA (793 uL, 3.68 mmol).After stirring at room temp for 30 minutes, the reaction was slowlyheated to 80° C., then to gentle reflux for two hours. Reaction wascooled and treated with tBuOH (1.675 mL, 17.52 mmol) and copper iodide(200 mg, 1.051 mmol) and heated back to reflux for 2 additional hours.Reaction was cooled (precipitation observed), diluted with DCM,filtered, and concentrated in vacuo. The crude product was purified byflash chromatography with a 100:0-0:50% A:B linear gradient (A=hexanes;B=ethyl acetate). Fractions containing product were pooled andconcentrated to give C7. Measured mass=486.

Synthesis of C8 (Ex. 23)

C7 (101 mg, 0.208 mmol) was dissolved in DCM (20 mL) and treated withTFA (20 mL). The reaction was aged for five minutes, after which solventand TFA were removed in vacuo to give C8 as a colorless oily solid thatwas used without further purification. Measured mass=286.

Synthesis of C9 (Ex. 24)

C8 (100.0 mg, 0.209 mmol) was suspended in chloroform (28 mL) andtreated with tetrabutylammonium hydrogen sulfate (70.9 mg, 0.209 mmol),N-methoxy carbonyl maleimide (98.0 mg, 0.631 mmol), and DIEA (88.0 μL,0.502 mmol). Saturated sodium bicarbonate (28 mL) was added. Thereaction was stirred vigorously for 25 hours, after which it wasextracted 3×50 mL DCM. The combined organic layers were dried withsodium sulfate, then evaporated to dryness. The crude product waspurified by flash chromatography with a 100:0-0:50% A:B linear gradient(A=hexanes; B=ethyl acetate). Fractions containing the desired productwere combined and evaporated to give C9. ¹H NMR (CDCl₃): 1.24-1.26 (m,28H), 1.55-1.59 (m, 4H), 3.50 (t, 4H J=7.4 Hz), 6.68 (s, 4H). Measuredmass=445.

Synthesis of C10 (Ex. 25)

C2 (12.0 mg, 1.31 μmol) was dissolved in 1:3 water:dioxane (14.4 mL) andwas treated with C9 (5.8 mg, 13.1 μmol) dissolved in 1.4 mL dioxane.After aging overnight, the reaction was quenched with N-methyl maleimide(4.38 mg, 39.4 μmol) and was diluted with DI Water. The crude reactionwas dialyzed once against DI water, filtered, and purified by RP-HPLC(95:5-5:95% A:B linear gradient (A=100 mM aqueous TEAA; B=100 mM TEAA inacetonitrile) Waters Phenyl xbridge Column). Fractions containingproduct were dialyzed against DI water and lyophilized to give C10.Measured mass: 9546.

Synthesis of C11-seq32 and C12-seq32-c (Ex. 26 and Ex. 27)

Conjugates C11-seq32 and C12-seq32-c were prepared in a manner analogousto that used for C4-seq32 and C6-seq32.

Additional Synthesis of C12-peptide Conjugates

Additional conjugates of C12 and peptide sequence were prepared in amanner analogous to that used for C12-seq32.

Section D Examples 28-30

Preparation of C13, C14-seq32 and C15-seq32

Scheme 9 shown in FIG. 10 A to FIG. 10D was used to prepare C13,C14-seq32 and C15-seq32-a.

Synthesis of C13 (Ex. 28)

C2 (11 mg, 1.22 μmol) dissolved in DI water (3.5 mL) was treated with C2bismaleimide (2.69 mg, 12.20 umol) dissolved in DMF (270 μL). After onehour, LC-MS indicated good conversion to desired product. Reaction wasdialyzed 3 times against DI water and lyophilized to give C13. Measuredmass: 9317.

Synthesis of C14-seq32 (Ex. 29)

C13 (10.53 mg, 1.13 μmol) was dissolved in DI water (50 μL) and dilutedwith TFE modified with 50 mM AcOH (2.0 mL), then was added to seq32(9.22 mg, 2.26 μmol) dissolved in 8M guanidine hydrochloride (60 μL).The reaction was aged for 10 minutes. Reaction was purified by AEX(95:5-55:45 A:B linear gradient (A=20 mM TEA in 60% aqueous TFE; B=1MCsCl and 20 mM TEA in 60% aqueous TFE), Dionix Propac column). Fractionscontaining product were dialyzed to give C14-seq32.

Synthesis of C15-seq32-c (Ex. 30)

C14-seq32 (9.81 mg, 0.738 μmol) dissolved in DI water (2.6 mL) wastreated with guide strand C5 (7.76 mg, 0.738 μmol) dissolved in DI water(751 μL). Solution was lyophilized to give the desired productC15-seq32-c. Measured mass=passenger strand: 13396, guide strand: 6868

Additional Synthesis of C15-peptide Conjugates

Additional conjugates of C15 and peptide sequence were prepared in amanner analogous to that used for C15-seq32.

Examples 31-33 Preparation of D1, D3 and D4

Scheme 10 as shown in FIG. 11A to FIG. 11 D was used to prepare D1, D3and D4.

Synthesis of D1 (Ex. 31) To a solution of NHS ester (100.0 mg, 0.320mmol) in 0.5 mL anhydrous DCE were added azido amine (253.0 mg, 0.480mmol) in 0.5 mL anhydrous DCE and 1.5 eq. triethylamine. The resultingsolution was stirred for 1 h at room temperature, and the reactionmixture was loaded on a silica column, eluding with MeOH/DCM=0/100 to10/90 over 25 min. The collected fraction was subject to LC-MS analysisand the result indicated >95% purity.

Synthesis of D3 (Ex. 32)

Oligonucleotide D2 (10 mg, 1.3 μmol) and azide linker D1 (5.6 mg, 7.8μmol) were dissolved in degassed 3:1 DMA/water (1000 μL) in an Eppendorftube, then a solution of copper(I) bromide-dimethyl sulfide (0.05 mg,0.26 μmol) in degassed MeCN (100 μL) was added to the reaction mixture.After 60 min at 40° C., D2 was completely consumed monitored by LC-MS.The reaction mixture was diluted with 0.4 M EDTA (5 mL) and stirred foradditional 15 min, then dialyzed against water using a Millipore 3Kmembrane and purified by RP HPLC (5%-60% A in B, A: 100 mM TEAA in MeCN,B: 100 mM TEAA in water). The product fractions were dialyzed againstwater and lyophilized to afford D3 as a white powder.

Synthesis of D4 (Ex. 33)

TetraGalNAc A10 (5.7 mg, 3.5 μmol), HATU (2.0 mg, 5.2 μmol),N,N-diisopropylethylamine (1.8 mg, 14 μmol) were dissolved in DMSO (100μL). After 10 min, the activated ester was added to oligonucleotide D3(6.4 mg, 0.70 μmol) in DMF (350 μL) and water (50 μL). The resultingreaction mixture was stirred for 15 min and quenched by addition ofwater, then purified by RP HPLC (5%-60% A in B, A: 100 mM TEAA in MeCN,B: 100 mM TEAA in water). The product fractions were dialyzed againstwater and lyophilized to afford R³ as a whiter powder.

Examples 34-35

Preparation of D5-seq32 and D7-seq32

Scheme 11 as shown in FIG. 12A-1 to FIG. 12B-2 was used to prepareD5-seq32 and D7-seq32.

Synthesis of D5-seq32 (Ex. 34)

Oligonucleotide D4 (6.5 mg, 0.60 μmol) in 200 μL formamide/pH=6.8 Trisbuffer=3/1 was treated with peptide seq32 (9.8 mg, 2.4 μmol) in 200 μLof the same buffer and the resulting reaction mixture was stirred for 1h. The reaction was diluted by addition of formamide 2.5 mL and purifiedby strong anion exchange chromatography on a Sepax Proteomix SAX NP10,21.2×50 mm column (2%-30% B in A over 8 min, A: 60:40trifluoroethanol:water, 40 mM triethylamine, B: 60:40trifluoroethanol:water, 40 mM triethylamine, 1 M guanidine-HCl, 20mL/min) to afford D5-seq32 as a white powder.

Synthesis of D7-seq32 (Ex. 35)

Oligonucleotide D5-seq32 (5.7 mg, 0.304 μmol) and the correspondingantisense strand D6 (2.0 mg, 0.29 μmol) were mixed in RNase free waterfor 1 h. The reaction mixture was lyophilized and the product D7-seq32-dwas submitted for in vivo evaluation.

Synthesis of Additional D7-peptide Conjugates.

Additional conjugates of D7 and peptide sequence were prepared in amanner analogous to that used for D7-seq32.

Section E. Synthesis of Hybrid of Lipid and Peptide Conjugates Examples36-42

Scheme 12 is shown in FIG. 13A to FIG. 13H-2.

Synthesis of E2 (Ex. 36)

Oligonucleotide E1 (300 mg, 39 μmol) and the PEG9 azide linker (58.5 mg,78 μmol) were dissolved in degassed 3:1 DMA/water (10 mL) in a glassvial, then a solution of copper(I) bromide-dimethyl sulfide (20.06 mg,98 μmol) in degassed DMSO (699 μL) was added to the reaction mixture.After 40 min at 45° C., E1 was completely consumed monitored by LC-MS.The reaction mixture was diluted with 0.4 M EDTA (20 mL) and stirred foradditional 15 min, then dialyzed against water using a Millipore 3Kmembrane and lyophilized to afford E2 as a white powder.

Synthesis of E3 (Ex. 37)

TetraGalNAc A10 (237 mg, 145 μmol), HATU (55.2 mg, 145 μmol),N,N-diisopropylethylamine (94 mg, 726 μmol) were dissolved in DMSO (700μL). After 10 min, the activated ester was added to oligonucleotide E2(306 mg, 36 μmol) in DMA (7.5 mL) and water (2.5 mL). The resultingreaction mixture was stirred for 15 min and quenched by addition ofwater, then purified by RP HPLC (5%-60% A in B, A: 100 mM TEAA in MeCN,B: 100 mM TEAA in water). The product fractions were dialyzed againstwater and lyophilized to afford E3 as a whiter powder.

Synthesis of E4 (Ex. 38)

To a solution of E3 (246 mg, 24 μmol, 1 eq.) in water (8000 μL) wasadded TCEP-HCl (70 mg, 244 μmol, 10 eq.). The reaction mixture was mixeduntil TCEP-HCl fully dissolved. The solution was left at roomtemperature for 2 hours. The solution was centrifugal dialyzed two timesagainst water over a 3K membrane to afford crude E4 which was directlyused in the next step.

Synthesis of E5 (Ex. 39)

To a solution of E4 (244 mg, 24 μmol) in water (12 mL) was addedN-(2-aminoethyl)maleimide trifluoroacetate salt (62.2 mg, 0.245 mmol, 10eq.) dissolved in MeCN (0.5 mL). The solution was left at roomtemperature for 1 hour. LCMS indicated complete conversion. The solutionwas centrifugal dialyzed twice against water over a 3K membrane andlyophilized to afford E5 as a white powder.

Synthesis of E6 (Ex. 40)

E5 (40 mg, 3.95 μmol, 1 eq.) was dissolved in 4:1 DMA/water (500 μL).DIPEA (10.2 mg, 79 μmol, 20 eq.) was added to the above solution.Cholesterol chloroformate (18 mg, 40 μmol, 10 eq.) was dissolved in THE(500 μL). The two solutions were mixed together, and the reactionmixture was left at room temperature for 1 hour. LCMS indicated that thereaction was done. The reaction mixture was purified by RP HPLC (5%-95%B in A, A: 100 mM TEAA in water, B: 100 mM TEAA in MeCN). The productfractions were dialyzed against water and lyophilized to afford E6 as awhiter powder.

Synthesis of E7 (Ex. 41)

To a solution of E6 (24.5 mg, 2.3 μmol, 1 eq.) in water (1000 μL) wasadded piperidine in DMF (200 μL, 20% by volume, 200 eq.). The reactionmixture was left at room temperature for 1 hour. LCMS indicated that thereaction was done. The reaction mixture was filtered (0.2 uM), dialyzedagainst water, and lyophilized to give E7 as a whiter powder.

Synthesis of E8 (Ex. 42)

E7 (16 mg, 1.55 μmol, 1 eq.) was dissolved in freshly prepared aqueoussodium bicarbonate (0.1M, 400 μL). SPDP (4.85 mg, 0.016 mmol, 10 eq.)was dissolved in acetonitrile (400 uL). The two solutions were mixedtogether, and the reaction mixture was left at room temperature for 1hour. The reaction mixture was purified by RP HPLC (5%-95% B in A, A:100 mM TEAA in water, B: 100 mM TEAA in MeCN). The product fractionswere dialyzed against water and lyophilized to afford E8 as a whiterpowder.

Examples 43-44 Preparation of E8-Seq 137 and E9-Seq 137

Scheme 13 is shown in FIG. 14A-1 to FIG. 14B-2.

Synthesis of E9-Seq137 (Ex. 43)

Oligonucleotide E8 (3.0 mg, 0.286 μmol) in 100 μL of 2 M Thiourea/20 mMMES in Formamide pH 6.5 was treated with peptide seq 137 (2.33 mg, 0.572μmol) in 100 μL of the same buffer and the resulting reaction mixturewas left at RT for 30 min. The reaction was diluted by addition offormamide 1 mL and purified by strong anion exchange chromatography on aPropac SAX 22×250 mm column (5%-45% B in A over 15 min, A: 60:40trifluoroethanol:water, 20 mM triethylamine, B: 60:40trifluoroethanol:water, 20 mM triethylamine, 1 M guanidine-HCl, 20mL/min) to afford E9-seq-137 as a white powder.

Synthesis of E10-Seq137-e (Ex. 44)

Passenger strand E9-seq137 (1.30 mg, 0.077 μmol) and the correspondingguide strand B7 (0.561 mg, 0.077 μmol) were mixed in RNase free waterand heated to 90° C. for 1 min, then left at RT for 10 min. The duplexwas lyophilized and the resulting product isolated as an amorphous whitepowder.

Synthesis of Additional E10-peptide Conjugates.

Additional conjugates of E10 and peptide sequence were prepared in amanner analogous to that used for E10-Seq137-e.

Section F. Preparation of 3, 13, 18 Tripeptide Conjugates Examples 45-49

Scheme 14 is shown in FIG. 15A to FIG. 15E-2.

Synthesis of Compound F2 (Ex. 45)

Compound A10 (210 mg, 0.129 mmol) was dissolved in dryN-methyl-2-pyrrolidinone (3 ml). HATU (48.9 mg, 0.129 mmol) and drydiisopropylethylamine (0.046 ml, 0.257 mmol) were added, and the mixturewas sonicated until the solid was fully dissolved. The reaction was leftat RT for 5 min. In a separate vial, compound F1 (500 mg, 0.0646 mmol)was dissolved in water (2 ml) and N-methyl-2-pyrrolidinone (5 ml). TheA10 solution was added to the F1 solution, and the reaction was left atRT for 5 min. The reaction mixture was loaded on to an HPLC fitted withan Agilent PL-SAX 8 um 50×150 mm column heated to 60° C. The product wasgradient eluted by starting at 100% solvent A (4:1 H₂O:ethanol, 20 mMtriethylammonium acetate pH 7.0) and increasing to 80% solvent B (4:1H₂O:ethanol, 20 mM triethylammonium acetate pH 7.0, 1M guanidiniumhydrochloride) over 30 min at 100 ml/min. The fractions were combined,and the ethanol content was reduced to 5% by diluting with water. Thesolution was pump loaded onto a Waters XBridge Sum 50×50 mm column at 50ml/min, and the product was washed with water at 100 ml/min for 5 min.The desalted product was eluted by reversing the column and flowing 2:3H₂O:acetonitrile at 50 ml/min through the column. The fraction wasfreeze dried to afford F2 as a white amorphous solid. Expected mass:9363.6, found mass: 9363.5.

Synthesis of Compound F3 (Ex. 46)

F2 (500 mg, 0.0534 mmol) and azido-peg9-amine (253 mg, 0.481 mmol) weredissolved in 2,2,2-trifluoroethanol (5 ml) and water (5 ml). Nitrogenwas bubbled through the solution for 1 min. In a separate vial,copper(I) bromide dimethyl sulfide (43.9 mg, 0.214 mmol) was dissolvedin acetonitrile (2.5 ml). Nitrogen was bubbled through the solution for1 min. The two solutions were mixed together, and nitrogen was bubbledthrough the reaction mixture for 1 min. The vial was sealed and left atRT for 1 hour. The reaction mixture was quenched with EDTA solution(0.5M, pH 8.0, 1 mL) and loaded onto an HPLC fitted with a WatersXBridge 5 um 50×250 mm column. The product was gradient eluted bystarting at 100% solvent A (H₂O, 0.1M triethylammonium acetate pH 7.0)and increasing to 40% solvent B (acetonitrile) at 100 ml/min over 30minutes. The fractions were combined, and the acetonitrile content wasreduced to 5% by diluting with water. The solution was pump loaded ontoa Waters XBridge Sum 50×50 mm column at 50 ml/min, and the product waswashed with water at 100 ml/min for 5 min. The desalted product waseluted by reversing the column and flowing 2:3 H₂O:acetonitrile at 50ml/min through the column. The fraction was freeze dried to afford F3 asa white amorphous solid. Expected mass: 10943.5, found mass: 10943.2.

Synthesis of Compound F4 (Ex. 47)

F3 (467 mg, 0.0427 mmol) was dissolved in sodium bicarbonate solution(0.1M, 4.5 mL). NHS-SPDP (120 mg, 0.384 mmol) was dissolved inacetonitrile (1 mL). The solutions were mixed together, and the reactionwas left at RT for 15 min. The reaction mixture was loaded onto an HPLCfitted with a Waters XBridge Sum 50×250 mm column. The product wasgradient eluted by starting at 100% solvent A (H₂O, 0.1Mtriethylammonium acetate pH 7.0) and increasing to 40% solvent B(acetonitrile) at 100 ml/min over 30 min. The fractions were combined,and the acetonitrile content was reduced to 5% by diluting with water.The solution was pump loaded onto a Waters XBridge Sum 50×50 mm columnat 50 ml/min, and the product was washed with water at 100 ml/min for 5min. The desalted product was eluted by reversing the column and flowing2:3 H₂O:acetonitrile at 50 ml/min through the column. The fraction wasfreeze dried to afford F4 as a white amorphous solid. Expected mass:11535.3, found mass: 11535.1.

Synthesis of F5-Seq 463 (Ex. 48)

Peptide Seq. 612 (8.75 mg, 0.00520 mmol) was dissolved in DMSO (1 mL)containing 20 mM acetic acid. In a separate vial, F4 (10 mg, 0.000867mmol) was dissolved in DMSO (1 ml) containing 20 mM acetic acid. The twosolutions were mixed together and left at RT for 1 hour. The reactionwas quenched with N-methylmaleimide (5.78 mg, 0.0520 mmol) and loadedonto an HPLC fitted with an Agilent PL-SAX 10 um 25×50 mm column. Theproduct was gradient eluted by starting at 100% solvent A (2:3H₂O:2,2,2-trifluoroethanol, 20 mM triethylamine) and increasing to 70%solvent B (2:3 H₂O:2,2,2-trifluoroethanol, 20 mM triethylamine, 0.5Mguanidinium hydrochloride) at 30 ml/min over 20 min. The fractions werecombined and loaded onto an HPLC fitted with a Waters XBridge Sum 19×250mm column. The product was gradient eluted by starting at 85% solvent A(H₂O, 0.1M hexylammonium acetate pH 7.0) and increasing to 65% solvent B(tetrahydrofuran) at 20 ml/min over 30 min. The fractions were combined,and the tetrahydrofuran content was reduced to less than 5% undervacuum. The solution was centrifugal dialyzed over a 10 k membrane onceagainst water, once against 4:1 H₂O:ethanol containing 0.1M sodiumchloride, and two more times against water. The concentrate was freezedried to afford F5-Seq 463 as a white amorphous solid. Expected mass:16247.8, found mass: 16247.9.

Example 49

Scheme 15 is shown in FIG. 16A-1 to FIG. 16B-2.

Synthesis of F6 Seq 463-f (Ex. 49)

F5-Seq 463 (7.75 mg, 0.000477 mmol) and Guide B7 (3.27 mg, 0.000477mmol) were dissolved in H₂O (0.5 mL). The solution was left at RT for 1hour and then freeze dried to afford the duplex of F6 Seq 463-f as awhite amorphous solid (11 mg, quantitative). Expected mass of passengerstrand: 16247.8, found mass: 16247.9. Expected mass of guide strand:6852.5, found mass: 6852.7.

Synthesis of Additional F10-Peptide Conjugates an Duplexes.

Additional conjugates of F10 and peptide sequences and their duplexeswere prepared in a manner analogous to that used for F6-Seq 463-f.

Section G. Preparation of 3,8,13,18 Tetrapeptides Examples 50-53

Scheme 16 is shown in FIG. 17A-1 to FIG. 17D-2.

Synthesis of G2 (Ex. 50)

A10 (210 mg, 0.129 mmol) was dissolved in dry N-methyl-2-pyrrolidinone(3 ml). HATU (48.9 mg, 0.129 mmol) and dry diisopropylethylamine (0.046ml, 0.257 mmol) were added, and the mixture was sonicated until thesolid was fully dissolved. The reaction was left at RT for 5 min. In aseparate vial, G1 (500 mg, 0.0643 mmol) was dissolved in water (2 ml)and N-methyl-2-pyrrolidinone (5 ml). The A10 solution was added to theG1 solution, and the reaction was left at RT for 5 min. The reactionmixture was loaded on to an HPLC fitted with an Agilent PL-SAX 8 um50×150 mm column heated to 60° C. The product was gradient eluted bystarting at 100% solvent A (4:1 H₂O:ethanol, 20 mM triethylammoniumacetate pH 7.0) and increasing to 80% solvent B (4:1 H₂O:ethanol, 20 mMtriethylammonium acetate pH 7.0, 1M guanidinium hydrochloride) over 30minutes at 100 ml/min. The fractions were combined, and the ethanolcontent was reduced to 5% by diluting with water. The solution was pumploaded onto a Waters XBridge Sum 50×50 mm column at 50 ml/min, and theproduct was washed with water at 100 ml/min for 5 min. The desaltedproduct was eluted by reversing the column and flowing 2:3H₂O:acetonitrile at 50 ml/min through the column. The fraction wasfreeze dried to afford the G2 as a white amorphous solid. Expected mass:9399.7, found mass: 9399.5.

Synthesis of G3 (Ex. 51)

G2 (483 mg, 0.0514 mmol) and azido-peg9-amine (324 mg, 0.617 mmol) weredissolved in 2,2,2-trifluoroethanol (5 ml) and water (5 ml). Nitrogenwas bubbled through the solution for 1 min. In a separate vial,copper(I) bromide dimethyl sulfide (50 mg, 0.244 mmol) was dissolved inacetonitrile (2.5 ml). Nitrogen was bubbled through the solution for 1min. The two solutions were mixed together, and nitrogen was bubbledthrough the reaction mixture for 1 min. The vial was sealed and left atRT for 1 hour. The reaction mixture was quenched with EDTA solution(0.5M, pH 8.0, 1 mL) and loaded onto an HPLC fitted with a WatersXBridge Sum 50×250 mm column. The product was gradient eluted bystarting at 100% solvent A (H₂O, 0.1M triethylammonium acetate pH 7.0)and increasing to 40% solvent B (acetonitrile) at 100 ml/min over 30min. The fractions were combined, and the acetonitrile content wasreduced to 5% by diluting with water. The solution was pump loaded ontoa Waters XBridge Sum 50×50 mm column at 50 ml/min, and the product waswashed with water at 100 ml/min for 5 min. The desalted product waseluted by reversing the column and flowing 2:3 H₂O:acetonitrile at 50ml/min through the column. The fraction was freeze dried to afford G3 asa white amorphous solid. Expected mass: 11506.2, found mass: 11506.0.

Synthesis of G4 (Ex. 52)

G3 (455 mg, 0.0396 mmol) was dissolved in sodium bicarbonate solution(0.1M, 5 mL). NHS-SPDP (160 mg, 0.512 mmol) was dissolved inacetonitrile (1.5 mL). The solutions were mixed together, and thereaction was left at RT for 15 min. The reaction mixture was loaded ontoan HPLC fitted with a Waters XBridge Sum 50×250 mm column. The productwas gradient eluted by starting at 100% solvent A (H₂O, 0.1Mtriethylammonium acetate pH 7.0) and increasing to 40% solvent B(acetonitrile) at 100 ml/min over 30 min. The fractions were combined,and the acetonitrile content was reduced to 5% by diluting with water.The solution was pump loaded onto a Waters XBridge Sum 50×50 mm columnat 50 ml/min, and the product was washed with water at 100 ml/min for 5min. The desalted product was eluted by reversing the column and flowing2:3 H₂O:acetonitrile at 50 ml/min through the column. The fraction wasfreeze dried to afford G4 as a white amorphous solid. Expected mass:12295.3, found mass: 12295.1.

Synthesis of G5-Seq 489 (Ex. 53)

Peptide SEQ ID NO: 489 (CIFGAIAGFIKNIWEGLI all (D)) (13.6 mg, 0.00694mmol) was dissolved in DMSO (1 mL) containing 20 mM acetic acid. In aseparate vial, G4 (10 mg, 0.000867 mmol) was dissolved in DMSO (1 ml)containing 20 mM acetic acid. The two solutions were mixed together andleft at RT for 1 hour. The reaction was quenched with N-methylmaleimide(7.71 mg, 0.0694 mmol) and loaded onto an HPLC fitted with an AgilentPL-SAX 10 um 25×50 mm column. The product was gradient eluted bystarting at 100% solvent A (2:3 H₂O:2,2,2-trifluoroethanol, 20 mMtriethylamine) and increasing to 70% solvent B (2:3H₂O:2,2,2-trifluoroethanol, 20 mM triethylamine, 0.5M guanidiniumhydrochloride) at 30 ml/min over 20 min. The fractions were combined andloaded onto an HPLC fitted with a Waters XBridge Sum 19×250 mm column.The product was gradient eluted by starting at 85% solvent A (H₂O, 0.1Mhexylammonium acetate pH 7.0) and increasing to 65% solvent B(tetrahydrofuran) at 20 ml/min over 30 min. The fractions were combined,and the tetrahydrofuran content was reduced to less than 5% undervacuum. The solution was centrifugal dialyzed over a 10 k membrane onceagainst water, once against 4:1 H₂O:ethanol containing 0.1M sodiumchloride, and two more times against water. The concentrate was freezedried to afford G5-Seq 489 as a white amorphous solid. Expected mass:19708.1, found mass: 19708.0.

Example 54

Scheme 17 is shown in FIG. 18A-1 to FIG. 18B-2.

Synthesis of G6-Seq 489-g (Ex. 54)

G5-Seq 489 (8.5 mg, 0.000434 mmol) and B7 (2.98 mg, 0.000434 mmol) weredissolved in H₂O (0.5 mL). The solution was left at RT for 1 hour andthen freeze dried to afford the duplex G6-Seq 489-g as a white amorphoussolid. Expected mass of passenger strand: 19708.1, found mass: 19708.3.Expected mass of guide strand: 6852.5, found mass: 6852.6.

Synthesis of Additional G6-peptide Conjugates and Duplexes.

Additional conjugates of G6 and peptide sequences and their duplexeswere prepared in a manner analogous to that used for G6-Seq 489-g.

Section H. Preparation of 3,8,13,18 tetrapeptide

Examples 55-58

Scheme 18 below was used to prepare H1 to H5.

Synthesis of H1 (Ex. 55)

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of di-tert-butyl1-(tert-butylthio)hydrazine-1,2-dicarboxylate (15 g, 46.8 mmol, 2.00equiv) in N,N-dimethylformamide (30 mL). A solution of2-aminoethanethiol hydrochloride (2.66 g, 23.4 mmol, 1 equiv) in N,N-dimethylformamide (80 ml) was added slowly into the round-bottomflask. This was followed by the addition of triethylamine (2.36 g, 23.4mmol, 1 equiv). After stirring at RT overnight, a white solid wasprecipitating. Dry N, N-dimethylformamide (100 ml) was added to obtain anearly clear solution. Triethylamine was added until a white solid wasprecipitating again. The reaction mixture was stirred at RT for 8 hours.The solution was filtered and evaporated under reduced pressure. Diethylether (200 ml) was added to the residue and filtered. The white solidwas collected and dried in dessicator. Afterward, this white solid wasdissolved five times in diethyl ether (5×10 ml), stirred for severalminutes and filtered. The desired product was obtained as a white solid.¹HNMR (CDCl₃, 500 MHz, ppm): 1.36 (s, 9H), 3.07 (t, 2H), 3.4 (t, 2H),8.3 (s, 2H).

Synthesis of H3 (Ex. 56)

Lithocholic acid (H2) (7 gm, 18.59 mmol, 1 equiv) was dissolved in drydichlormethane (200 ml) and then cooled to 0° C. Following this N,N-dicyclohexylcarbodiimide (4.6 g, 22.31 mmol, 1.2 equiv) was added tothe solution. After stirring for 30 min at 0° C., pentafluorophenol(3.76 gm, 20.45 mmol, 1.1 equiv) in dichloromethane (13 ml) was added.Stirring was then continued at RT under argon for an additional 20 h.The precipitated N, N-dicyclohexylurea was filtered off and washed withcold dichloromethane. Combined filterates were then evaporated underreduced pressure. The oily residue obtained was then diluted withdichloromethane (50 ml) and washed with sat. aq. NaCl (60 ml) and water(80 ml). The organic phase was dried over Na₂SO₄, filtered andevaporated to dryness. The dried compound was purified using columnchromatography (elution with CH₂Cl₂/CH₃OH, 100/0-97/3). MS (m/z); 566[M+Na]⁺

Synthesis of H4 (Ex. 57)

Compound H3 (4.5 gm, 8.29 mmol, 1 equiv) was dissolved in drydichloromethane (15 ml) and then cooled to 0° C. A cold mixture of2-(tert-butyldisulfanyl)ethanamine (H1) (2.057 gm, 12.44 mmol, 1.5equiv) and triethylamine (2.56 gm, 2.52 mmol, 3 equiv) indichloromethane (7 ml) was added to the resulting solution. The reactionmixture was stirred at RT for 2 h. TLC confirmed the formation ofproduct. The reaction mixture was washed with sat. aq. NaCl (20 ml×2)and water (20 ml×2). The organic phase was dried over Na₂SO₄, filteredand dried over vacuum. The crude product was purified via silica gelcolumn chromatography (elution with CH₂Cl₂/CH₃OH, 100/0-95/5) yieldingpure compound H4. MS (m/z); 524.35, [M+1]⁺

Synthesis of H5 (Ex. 58)

H4 (3 gm, 5.73 mmol, 1 equiv) was dissolved in dry dichloromethane (15ml) and triethylamine was added (0.869 g, 8.59 mmol, 1.5 equiv). Thereaction mixture was cooled to 0° C. 2-Cyanoethyl-N,N-diisopropylaminochlorophosphite (2.71 gm, 11.45 mmol, 2 equiv) in drydichloromethane (10 ml) was added dropwise to the reaction mixture. Theresulting solution was stirred for 1 h. TLC confirmed the formation ofproduct. The reaction mixture was evaporated and purified on silica gelcolumn (elution with hexanes/ethylacetate/triethylamine, 100/0/1.5 to60/40/1.5). MS (m/z); 724.46 [M+1]⁺ ³¹P NMR (CDCl₃, 500 MHz, ppm); 146.5

Examples 59-66

Scheme 19 as shown in FIG. 19A to FIG. 19I-2 was used to prepare Ex. 59to Ex. 66.

Synthesis of H6 (Ex. 59)

See synthesis of B2 for reaction procedure. Expected mass: 9609.071,found mass: 9605.

Synthesis of H7 (Ex. 60)

To a solution of H6 (15 mg, 1.56 umol, 1 eq) in water (1400 ul) wasadded TCEP-HCl (26.8 mg, 0.094 mmol, 60 eq). The reaction mixture wasmixed until TCEP-HCl fully dissolved. The solution was left at RTovernight. The solution was centrifugal dialyzed two times against waterover 3K membrane. Expected mass:9520, found mass: 9517.

Synthesis of H8 (Ex. 61)

See synthesis of B9 for reaction procedure. Expected mass: 9630, foundmass: 9627.

Synthesis of H9-Seq32 (Ex. 62)

See the synthesis of B10-seq32 for reaction procedure. Expected mass:13597, found mass: 13598.

Synthesis of H7-Seq32-h (Ex. 63)

See the synthesis of B11-seq32 for reaction procedure.

Synthesis of H8 (Ex. 64)

See the synthesis of C13 for reaction procedure. Expected mass: 9741.

Synthesis of H9-Seq32 (Ex. 65)

See the synthesis of C14 for reaction procedure. Expected mass: 13819,found mass: 13820.

Synthesis of H10-Seq32-h (Ex. 66)

See the synthesis of C15-Seq32 for reaction procedure.

Additional Synthesis of H7 and H10 Peptide Conjugates

Additional conjugates of H7 and H10 and peptide sequences and theirduplexes were prepared in a manner analogous to that used for H7-Seq32-hand H10-Seq32-h.

Section I. Preparation of 3,13,18 Trienzymatic Cleavable Linker PeptideConjugates Examples 67-73

Scheme 20 is shown in FIG. 20A-1 to FIG. 20E-2.

Synthesis of I3 (Ex. 67)

I1 (160 mg, 0.209 mmol) and 12 (48.8 mg, 0.219 mmol) were dissolved inDMA (1 mL) and were treated with N-methylmorpholine (46 μL, 0.417 mmol).The reaction was stirred at RT for 6 hours, then purified by RP-HPLC(95:5-20:80% A:B linear gradient (A=0.1% aqueous TFA; B=0.1% TFA inacetonitrile) Waters C18 xbridge Column 19×250 mm). Fractions containingI3 were extracted with 2:1 DCM:MeOH, dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the product. Measured mass=814.3

Synthesis of I4 (Ex. 68)

I3 (88 mg, 0.108 mmol) was dissolved in DMA (1 mL) and was treated withpiperidine (200 μL, 2.02 mmol) and stirred at 10° C. for 10 min. TFA(156 μL, 2.02 mmol) was added to quench the reaction. The reactionmixture was purified by RP-HPLC (95:5-60:40% A:B linear gradient (A=0.1%aqueous TFA; B=0.1% TFA in acetonitrile) Waters C18 xbridge Column30×250 mm). Fractions containing 14 were lyophilized to give theproduct. Measured mass=592.3.

Synthesis of I5 (Ex. 69)

I4 (912 mg, 1.324 mmol) was dissolved in DMSO (7.7 mL) and treated withL1 (1.0 g, 1.40 mmol) and DIEA (463 μL, 2.65 mmol). The reaction mixturewas stirred for 15 min and was purified by RP-HPLC (100:0-0:100% A:Blinear gradient (A=0.1% aqueous TFA; B=0.1% TFA in acetonitrile) WatersC18 xbridge column. Fractions containing I5 were lyophilized to give theproduct. Measured mass=609.5 [M+2]

Synthesis of I7 (Ex. 70)

I6 (500 mg, 0.065 mmol) and 15 (236 mg, 0.194 mmol) were dissolved in apH 5.5 MES buffer (51.6 ml, 500 mM) and acetonitrile (12.91 ml). Thesolution was degassed with nitrogen for 10 min, after which it wastreated with CuBr.SMe₂ (133 mg, 0.646 mmol) and degassed for anadditional five minutes with nitrogen. The reaction mixture wassonicated and stirred for 30 min, then purified by RP-HPLC (95:5-5:95%A:B linear gradient (A=100 mM aqueous TEAA; B=100 mM TEAA inacetonitrile) Waters Phenyl xbridge Column). Fractions containingproduct were dialyzed twice against 0.32M EDTA pH 6.5 over a 3Kmembrane, then three times against water. The concentrate was thendialyzed twice against 200 mM TEAA and then three times against water.The concentrate was lyophilized to give the product as an amorphouswhite solid. Measured mass=11400

Synthesis of I8 (Ex. 71)

I7 (287 mg, 0.025 mmol) was suspended in water (100 uL) and diluted withNMP (2.0 mL), which produced a homogeneous solution upon standing. HATU(13 mg, 0.035 mmol) was dissolved in NMP (200 uL) and was added to A10(62 mg, 0.038 mmol). The reaction mixture was diluted with NMP (200 uL)and was then treated with DIEA (13 uL, 0.076 mmol). The HATU reactionmixture was then added to the RNA solution in one portion and aged for10 min. Reaction was diluted with DI water and purified by RP-HPLC(95:5-5:95% A:B linear gradient (A=100 mM aqueous TEAA; B=100 mM TEAA inacetonitrile) Waters Phenyl xbridge Column). Fractions containing 18were dialyzed three times against water over a 3K membrane. Theconcentrate was lyophilized to give the product as an amorphous whitesolid. Measured mass=13027.

Synthesis of I9-Seq 1681 (Ex. 72)

I8 (20 mg, 1.537 μmol) was dissolved in TFE modified with 50 mM AcOH (2mL). In a separate vial, Seq ID 1681 (8.63 mg, 6.15 umol) was suspendedin 8M Gn.HCl (400 uL) and was diluted with 50 mM AcOH in TFE (2 mL) toform a slightly cloudy suspension, then added to the RNA solution. After10 min, more Seq ID 1681 (8.63 mg, 1.54 umol) was added and the reactionwas aged 30 min, after which AEX indicated near-complete conversion todesired product. Reaction was quenched with N-methylmaleimide (6.83 mg,61.5 μmol) and was purified by AEX (0-40% 1M Gn.HCl in 1:1 water:TFEwith 40 mM TEAA pH 7.5, Proteomix NP10 column heated to 60° C.).Material was repurified using 70:30-25:75 gradient of 200 mM HAA pH 7.5:ACN and an Agilent PLRP-S column. Pure fractions were pooled, dialyzed,and lyophilized to give I9-Seq 1681 (6.37 mg, 0.302 μmol, 19.65% yield).

Synthesis of I10-Seq 1681-f (Ex. 73)

I9-seq 1681 (3.02 mg, 0.143 μmol) was dissolved in water (950 μl) andwas treated with a solution of B7 (0.980 mg, 0.143 μmol) in water (144μl). The reaction mixture aged for 15 min and was then lyophilized togive the product as an amorphous white solid. Measured mass=21107.

Additional Synthesis of I10 Peptide Conjugates an Duplexes.

Additional conjugates of I10 and peptide sequences and their duplexeswere prepared in a manner analogous to that used for I10-seq-1681-f.

Section J. Preparation of Amino Modified C2 Linkers Examples 74-82

Scheme 21 is shown in FIG. 21A to FIG. 21H-2.

Synthesis of A10B (Ex. 74)

In a test tube equipped with a stir bar, A10 (100 mg, 0.061 mmol) wasdissolved in DMSO (611 μl) followed by the addition of Hunig's Base (133μl, 0.764 mmol) and HATU (76 mg, 0.199 mmol). After 20 min,N-(2-aminoethyl)maleimide trifluoroacetate salt (12.85 mg, 0.092 mmol)dissolved in 400 μL of DMSO was added. After 20 min, the reaction wasdetermined complete and quenched with water (1.5 mL) until yellow coloralmost dissipated. The reaction was purified by reverse phasechromatography (Gilson 2020, Solvent A) 0.1% TFA in water/Solvent B)0.1% TFA in ACN, 0-50% gradient for 15 min, 40 mL/min, XBridge Prep C185 μm OBD 30×250 mm). The resulting fractions were lyophilized to afforda white solid, A10B. [M+1, expected]=1757.807, [M+1, observed]=1759.0.

Synthesis of J2 (Ex. 75)

See Synthesis of B3 for reaction procedure. J2 [M+1, expected]=7604.750,[M+1, observed]=7600.0.

Synthesis of J3 (Ex. 76)

A10B (10.26 mg, 5.84 μmol) was dissolved in water (700 μL) and added toa 1.8 mL solution (1 water: 1 acetate buffer: 2 formamide) of J2 (29.6mg, 3.89 μmol). The reaction was shaken at RT for 20 min and thendetermined complete. The reaction mixture was purified using stronganion exchange chromatography (Gilson PLC 2020, Sepax Proteomix SAX NP1021.2×50 mm, Buffer A: 3:2 trifluoroethanol:water, 40 mMtriethylamine/Buffer B: 3:2 trifluoroethanol:water, 40 mM triethylamine,1000 mM guanidine-HCl, 1% B hold for 3 minutes, then 5% B-45% B over 12minutes). The fractions were dialyzed three times against water over a3K membrane to afford a white solid, J3. [M+1, expected]=9362.556, [M+1,observed]=9359.0.

Synthesis of J4 (Ex. 77)

To an Eppendorf vial, J3 (6.34 mg, 0.678 μmol) was dissolved in water(250 μL). In a separate Eppendorf vial, N-succinimidyl3-(2-pyridyldithio) propionate (SPDP) (0.831 mg, 2.035 μmol) wasdissolved in DMSO (50 μL). The SPDP solution was added to the RNAsolution. After 4 hours, the reaction was recharged with additional SPDP(2.77 mg, 6.78 μmol) which was dissolved in 50 μL DMSO. After 24 hr, thereaction was recharged with additional SPDP (2.77 mg, 6.78 μmol) whichwas dissolved in 50 μL DMSO. After 72 hr, the reaction was diluted to 3mg/mL with the addition of 390 μL of pH 8.1 sodium bicarbonate. After 2hr, an additional 3 eq. of SPDP in 50 μL DMSO were added. The reactionmixture was dialyzed three times against water over a 3K membrane andlyophilized to afford a white solid, J4. [M+1, expected]=9543.834, [M+1,observed]=9554.0.

Synthesis of J5-Seq26 (Ex. 78)

See Synthesis of B10-Seq32 for reaction procedure. J5-Seq26—Massobserved: 11413.

Synthesis of J6-Seq26-i (Ex. 79)

See Synthesis of B11-Seq32-b for reaction procedure. J6-Seq26-1—Massobserved: 18265.

Synthesis of J7 (Ex. 80)

To an Eppendorf vial, J3 (5.8 mg, 0.621 μmol) was dissolved in water(250 μL). In a separate Eppendorf vial,Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC)(0.727 mg, 1.862 μmol was dissolved in DMSO (50 μL) and the pH wasadjusted to pH 5 with the addition of 1 small drop of TFA. The SMCCsolution was added to the RNA solution. After several hours, the pH wastitrated to pH 7 with the gradual addition of 0.1N NaOH. After 18 hr, 6eq. of SMCC were dissolved in 50 μL DMSO and added to the reactionmixture. After 4 hr, an additional 3 eq. of SMCC in 50 μL DMSO was addedto the reaction. After several hr, 300 μL of pH 8.1 sodium bicarbonatesolution was added to the reaction. The reaction was dialyzed threetimes against water over a 3K membrane and lyophilized to afford a whitesolid, J7. [M+1, expected]=9543.834, [M+1, observed]=9554.0.

Synthesis of J8-Seq26 (Ex. 81)

See Synthesis of B10-Seq32 for reaction procedure. J8-Seq26—Massobserved: 11545.

Synthesis of J9-Seq26-i (Ex. 82)

See Synthesis of B11-Seq32 for reaction procedure. J9-Seq26-I—Massexpected: 18397.

Additional Synthesis of J6 & J9 Peptide Conjugates.

Additional conjugates of J6 and J9 and peptide sequences and theirduplexes were prepared in a manner analogous to that used for J6-Seq26,J9-Seq26 and J6-Seq26-i, J9-Seq26-i.

Section K. 3′ Bis Peptide Linkers

Examples 83-87

Scheme 22 is shown in FIG. 22A-1 to FIG. 22D-2.

Synthesis of K2 (Ex. 83)

In a 20 mL vial, 3-(tritylthio)propanoic acid (158 mg, 0.454 mmol) wasdissolved in DMF (1.514 mL) followed by the addition of HATU (184 mg,0.484 mmol) and Hunig's base (0.158 mL, 0.908 mmol). The reactionsolution turned light yellow in color. After 5 min, K1 (100 mg, 0.151mmol) was added as a solid and the reaction solution turned transparentorange in color. The reaction was stirred at RT for 15 min and thendetermined complete.

The reaction was purified by reverse phase chromatography (Gilson 2020,5-95% ACN/Water with a 0.1% TFA modifier, flow rate: 20 mL/min, gradienttime: 22 min, column: XBridge prep OBD 5 μm C18 19×250 nm). Theresulting fractions were lyophilized to afford a white solid, K2. [M+1,expected]=877.059, [M+1, observed]=877.4

Synthesis of K3 (Ex. 84)

In an Eppendorf vial, K2 (10.07 mg, 0.011 mmol) was dissolved informamide (0.5 mL). In a 15 mL Falcon tube, peptide Seq ID 74 (57.92 mg,0.034 mmol) was dissolved in formamide (1 mL). The peptide/formamidesolution was added to the linker/formamide solution and stirred at RTfor 20 min.

The reaction was determined complete and the reaction was purified byreverse phase chromatography (Gilson 2020, 5-100% ACN/Water with a 0.1%TFA modifier, flow rate: 20 mL/min, gradient time: 30 minutes, column:XBridge prep OBD 5 μm C18 19×250 nm). The resulting fractions werelyophilized to afford a white solid, K3. [M+3, expected]=1416.03, [M+3,observed]=1415.0

Synthesis of K4 (Ex. 85)

In a 40 mL vial, a solution of TFA (1000 μL), water (96 μL), andtriisopropylsilane (96 μL) in a 0.83:0.08:0.08 mixture by volume wascombined and added to K3 (47 mg, 0.011 mmol) in a 20 mL vial which wasstirred at RT for 10 min. An additional 500 μL of TFA was added and thereaction was stirred for an additional 10 min. The reaction wasdetermined complete, concentrated under reduced pressure, diluted with3.5 mL of 2M thiourea pH 6.5 in FMD and MES, and purified by reversephase chromatography (Gilson 2020, 5-80% ACN/Water with a 0.1% TFAmodifier, flow rate: 20 mL/min, gradient time: 20 minutes, column:XBridge prep OBD 5 μm C18 19×250 nm). The resulting fractions werelyophilized to afford a white solid, K4. [M+3, expected]=1334.34, [M+3,observed]=1334.4

Synthesis of K5-Seq 74 (Ex. 86)

See Synthesis of B10-Seq32 for reaction procedure. K5-Seq 74—Expectedmass: 13178.103.

Synthesis of K6-Seq 74-b (Ex. 87)

See Synthesis of B10-Seq32 for reaction procedure. Observed masspassenger=15907; Observed mass guide=8744; duplex=24651.

Additional Synthesis of K5 Peptide Conjugates and duplexes.

Additional conjugates of K5 and peptide sequences and the correspondingduplexes were prepared in a manner analogous to that used for K5-Seq 74and K6-Seq 74-b.

Section L. Preparation of Guide Strand Position 2′-10,15 ECL PeptideConjugates Examples 88-94

Scheme 23 is shown below, and in FIG. 23A to FIG. 23C-2.

Synthesis of L3 (Ex. 88)

(9H-fluoren-9-yl)methyl((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamateL1 (500 mg, 0.652 mmol), 2-(pyridin-2-yldisulfanyl)ethanaminehydrochloride (153 mg, 0.685 mmol), and N-methylmorpholine (0.143 mL,1.30 mmol) were dissolved in N,N-Dimethylacetamide (3 mL). The reactionmixture was aged for 16 h at RT and purified by reverse phasechromatography on a Waters Xbridge C18 column (5 uM, 30×250 mm) using agradient of 5-80% ACN/water with 0.1% TFA over 20 min at 40 mL/min. Theproduct was lyophilized to give L3 as a solid. MS(m z): 814 (M+1).

Synthesis of L4 (Ex. 89)

(9H-fluoren-9-yl)methyl((S)-3-methyl-1-oxo-1-(((S)-1-oxo-1-((4-((((2-(pyridin-2-yldisulfanyl)ethyl)carbamoyl)oxy)methyl)phenyl)amino)-5-ureidopentan-2-yl)amino)butan-2-yl)carbamateL3 (343 mg, 0.421 mmol) and piperidine (200 uL, 2.02 mmol) weredissolved in N,N-Dimethylacetamide (3 mL). The reaction mixture was agedfor 10 min at RT, quenched with trifluoroacetic acid (156 uL, 2.02mmol), and purified by reverse phase chromatography on a Waters XbridgeC18 column (5 uM, 30×250 mm) using a gradient of 5-40%acetonitrile/water with 0.1% trifluoroacetic acid over 20 min at 40mL/min. The product was lyophilized to give L4 as a solid. MS(m z): 592(M+1).

Synthesis of L6 (Ex. 90)

To a solution of4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl(2-(pyridin-2-yldisulfanyl)ethyl)carbamate L4 (238 mg, 0.346 mmol) indimethylsulfoxide (1.5 mL) was added a solution ofbis(2,5-dioxopyrrolidin-1-yl) octanedioate L5 (509 mg, 1.382 mmol) andtriethylamine (0.096 mL, 0.691 mmol). The reaction mixture was aged for15 min and purified on a silica gel column (80 g) using a gradient of1-10% methanol/dichloromethane over 30 min at 60 mL/min to give L6 as asolid. MS(m z): 845 (M+1)

Synthesis of L8 (Ex. 91)

RNA compound L7 (163 mg, 0.024 mmol) and 2-azidoethanamine hydrochloride(30 mg, 0.245 mmol) were dissolved in an argon degassed, 3:1 mixture ofN,N-Dimethylacetamide:water (2 mL). An argon degassed solution of copper(I) bromide dimethyl sulfide complex (12 mg, 0.059 mmol) was added andthe mixture was aged at 45° C. for 16 h. The mixture was quenched with a0.5 M solution of EDTA (3 mL) and let stand for 15 min. The product wasisolated by spin dialysis against water (3×) followed by lyophilizationto give a solid. MS(m z): 7086.

Synthesis of L9 (Ex. 92)

RNA compound L8 (46 mg, 6.49 μmol) and N-methylmorpholine (7.1 mL, 65μmol) were dissolved in water (250 μL) and DMSO (250 μL) at 10° C. Tothis mixture was added a solution of 2,5-dioxopyrrolidin-1-yl8-(((S)-3-methyl-1-oxo-1-(((S)-1-oxo-1-((4-((((2-(pyridin-2-yldisulfanyl)ethyl)carbamoyl)oxy)methyl)phenyl)amino)-5-ureidopentan-2-yl)amino)butan-2-yl)amino)-8-oxooctanoateL6 (18 mg, 21 μmol) dissolved in DMSO (500 μL). The reaction mixture wasaged for 16 h, diluted with water (1.5 mL) and purified by ion pairingchromatography on a Waters Xbridge phenyl column (5 pM, 19×250 mm) usinga gradient of 0-55% acetonitrile/water with 100 mM triethylammoniumacetate over 15 min at 20 mL/min. The product was isolated by spindialysis against water (3×) followed by lyophilization to give a solid.MS(m z): 8547.

Synthesis of L10-Seq 463 (Ex. 93)

RNA compound L9 (11 mg, 1.29 μmol) was dissolved in trifluoroethanolcontaining 50 mM acetic acid (500 μL). To this solution was addedpeptide Seq 463 (8.66 mg, 5.15 μmol) dissolved in trifluoroethanolcontaining 50 mM acetic acid (1000 μL). The mixture was aged for 10 min,quenched with N-methylmaleimide (1.9 mg, 44 μmol), and purified by ionpairing chromatography on a Waters Xbridge phenyl column (10 pM, 19×250mm) using a gradient of 5-95% acetonitrile/water with 100 mMtriethylammonium acetate over 15 min at 20 mL/min. The product wasisolated by spin dialysis against water (3×) followed by lyophilizationto give a solid. MS(m z): 11687.

Synthesis of L11-Seq 463-j (Ex. 94)

A solution of L10-Seq 463 (2.46 mg, 0.27 μmol) dissolved in DI water(300 μL) was added to B2 (3.1 mg, 0.27 μmol) and heated at 90° C. for 1min. Solution was lyophilized to give duplex as a whilte solid. MS(m z)passenger strand: 9267, guide strand:11686.

Additional Synthesis of L10 Peptide Conjugates and L11 Duplexes.

Additional L10 conjugates of peptide sequences and the correspondingduplexes L11 were prepared in a manner analogous to that detailed above.

Section M. Synthesis of Guide Strand Position 2′-10,15 Disulfide PeptideConjugates

Examples 95-98

Scheme 24 is shown in FIG. 24A-1 to FIG. 24B-2.

Synthesis of M1 (Ex. 95)

3-(Pyridin-2-yldisulfanyl)propanoic acid (506 mg, 2.35 mmol),2-azidoethanamine hydrochloride (317 mg, 2.59 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (496 mg, 2.59 mmol),1-hydroxy-7-azabenzotriazole (199 mg, 1.46 mmol), and n-methylmorpholine(0.44 mL, 4.7 mmol) were dissolved in dichloromethane (25 mL). Themixture was aged for 1 h, diluted with saturated sodium bicarbonatesolution (25 mL) and organic layer separated. Extracted aqeuous laterwith dichloromethane (2×25 mL), dried combined organics over anhydroussodium sulfate, filtered off solids and concentrated in vacuo. Themixture was purified on a silica gel column (80 g) using a gradient of0-50% ethyl acetate/dichloromethane over 15 min at 30 mL/min to give aclear oil of M1. MS(m z): 284.

Synthesis of M2 (Ex. 96)

RNA compound L7 (180 mg, 26 μmol) and M1 (59 mg, 208 μmol) weredissolved in a 100 mM, pH 5.5 MES buffer (3.6 mL) and acetonitrile (0.9mL). This mixture was degassed with argon for 15 min. To this solutionwas added a degassed solution of copper (I) bromide dimethyl sulfidecomplex (13 mg, 65 μmol) dissolved in acetonitrile (0.45 mL) and aged atRT for 28 h. The mixture was quenched with a 100 mM, pH 8 solution ofEDTA (5 mL) and allowed to stand for 15 min. The mixture was purified byion pairing chromatography on a Waters Xbridge phenyl column (5 pM,30×150 mm) using a gradient of 0-30% acetonitrile/water with 100 mMtriethylammonium acetate over 15 min at 30 mL/min. The product wasisolated by spin dialysis against water (3×) followed by lyophilizationto give a solid of M2. MS(m/z): 7481.

Synthesis of M3-Seq 463 (Ex. 97)

RNA compound M2 (27.3 mg, 3.65 μmol) was dissolved in trifluoroethanolcontaining 50 mM acetic acid (1300 μL). To this solution was addedpeptide Seq 463 (15.4 mg, 9.13 μmol) dissolved in trifluoroethanolcontaining 50 mM acetic acid (1300 μL). The mixture was aged for 10 min,quenched with N-methylmaleimide (10.1 mg, 91 μmol), and purified by ionpairing chromatography on a Waters Xbridge phenyl column (10 μM, 19×250mm) using a gradient of 5-80% acetonitrile/water with 100 mMtriethylammonium acetate over 15 min at 20 mL/min. The product wasisolated by spin dialysis against water (3×) followed by lyophilizationto give a solid of M3-Seq 463. MS(m z): 10624.

Synthesis of M4-Seq 463-j (Ex. 98)

A solution of B2 (2.18 mg, 0.24 μmol) dissolved in DI water (290 μL) wasadded to M3-Seq 463 (2.5 mg, 0.24 μmol) and heated at 90° C. for 1 min.This solution was lyophilized to give duplex M4-Seq 463-j as a whiltesolid. MS(m z) passenger strand: 9267, guide strand:10621

Additional Synthesis of M3 Peptide Conjugates and M4 Duplexes.

Additional M3 conjugates of peptide sequences and the correspondingduplexes M4 were prepared in a manner analogous to that detailed above.

Section N. Synthesis of Guide Strand Position 2′-15 Disulfide PeptideConjugates Examples 99-100

Scheme 25 is shown in FIG. 25A to FIG. 25B-2.

Synthesis of N3-Seq 283 (Ex. 99)

RNA compound N2 (11 mg, 1.54 μmol; prepared as detailed in Section M forthe di-click substrate) was dissolved in trifluoroethanol containing 50mM acetic acid (1300 μL). To this solution was added peptide seq283(3.57 mg, 2.31 μmol) dissolved in trifluoroethanol containing 50 mMacetic acid (1300 μL). The mixture was aged for 10 min, and purified byion pairing chromatography on a Waters Xbridge phenyl column (10 μM,19×250 mm) using a gradient of 5-80% acetonitrile/water with 100 mMtriethylammonium acetate over 15 min at 20 mL/min. The product wasisolated by spin dialysis against water (3×) followed by lyophilizationto give a solid. MS(m z): 8600.

Synthesis of N4-Seq 283-k (Ex. 100)

A solution of B2 (5.65 mg, 0.609 μmol) dissolved in DI water (423 μL)was added to N3-Seq 283 (5.24 mg, 0.609 μmol) and heated at 90° C. for 1min. Solution was lyophilized to give duplex as a whilte solid. MS(m z)passenger strand: 9268, guide strand:8601.

Additional Synthesis of N3 Peptide Conjugates and N4 Duplexes.

Additional N3 conjugates of peptide sequences and the correspondingduplexes N4 were prepared in a manner analogous to that detailed above.

Section O. Synthesis of Guide Strand Position 2′-15 ECL PeptideConjugates Examples 101-103

Scheme 26 is shown in FIG. 26A-1 to FIG. 26B-2.

Synthesis of O2 (Ex. 101)

RNA compound 01 (20.7 mg, 2.97 μmol; prepared in an analogous manner toL8) was dissolved in 100 mM NaHCO₃ (400 μL) and DMSO (300 μL). To thismixture was added a solution of 2,5-dioxopyrrolidin-1-yl8-(((S)-3-methyl-1-oxo-1-(((S)-1-oxo-1-((4-((((2-(pyridin-2-yldisulfanyl)ethyl)carbamoyl)oxy)methyl)phenyl)amino)-5-ureidopentan-2-yl)amino)butan-2-yl)amino)-8-oxooctanoateL6 (6.28 mg, 7.43 μmol) dissolved in DMSO (250 μL). The reaction mixturewas aged for 1.5 h, diluted with water (1.5 mL) and purified by ionpairing chromatography on a Waters Xbridge phenyl column (5 μM, 19×250mm) using a gradient of 0-60% acetonitrile/water with 100 mMtriethylammonium acetate over 15 min at 20 mL/min. The product wasisolated by spin dialysis against water (3×) followed by lyophilizationto give a solid. MS(m z): 7696.

Synthesis of O2-Seq 463 (Ex. 102)

RNA compound O2 (10 mg, 1.30 μmol) was dissolved in trifluoroethanolcontaining 50 mM acetic acid (1000 μL). To this solution was addedpeptide Seq 463 (3.28 mg, 1.95 μmol) dissolved in trifluoroethanolcontaining 50 mM acetic acid (500 μL). The mixture was aged for 1 hr andpurified by ion pairing chromatography on a Waters Xbridge phenyl column(5 μM, 19×250 mm) using a gradient of 5-90% acetonitrile/water with 100mM triethylammonium acetate over 15 min at 20 mL/min. The product wasisolated by spin dialysis against water (3×) followed by lyophilizationto give a solid. MS(m z): 9268.

Synthesis of O3-Seq 463-k (Ex. 103)

A solution of O2-Seq 463 (3.02 mg, 0.326 μmol) dissolved in DI water(303 μL) was added to B2 (3.02 mg, 0.326 μmol) and heated at 90° C. for1 min. Solution was lyophilized to give duplex as a whilte solid. MS(mz) passenger strand: 9267, guide strand:9264.

Additional Synthesis of O2 Peptide Conjugates and O3 Duplexes.

Additional O2 conjugates of peptide sequences and the correspondingduplexes O3 were prepared in a manner analogous to that detailed above.

Section P. Synthesis of Guide Strand Position 2′-15 Cholesterol andPeptide Conjugates Examples 104-106

Scheme 27 is shown in FIG. 27A-1 to FIG. 27B-2.

Synthesis of P1 (Ex. 104)

RNA compound N2 (67.2 mg, 9.39 μmol) and diisopropylethylamine (13.1 μL,75 μmol) was dissolved in water (750 μL), N,N-dimethylacetamide (750μL), and tetrahydrofuran (1200 μL). To this mixture was added a solutionof thiocholesterol (30.2 mg, 75 μmol) dissolved in tetrahydrofuran (300μL). The mixture was aged for 30 min, diluted with 2M triethylammoniumacetate (100 μL), and purified by ion pairing chromatography on a WatersXbridge phenyl column (10 μM, 19×250 mm) using a gradient of 5-95%acetonitrile/water with 100 mM triethylammonium acetate over 15 min at20 mL/min. The product was isolated by spin dialysis against water (3×)followed by lyophilization to give a solid. MS(m z): 7451.

Synthesis of P2-Seq 32-k (Ex. 105)

A solution of P1 (1.0 mg, 0.134 μmol) dissolved in DI water (200 μL) wasadded to B10-Seq 32 (1.86 mg, 0.129 μmol) and heated at 90° C. for 1min. Solution was lyophilized to give duplex as a whilte solid. MS(m z)passenger strand: 13295, guide strand:7450.

Synthesis of P2-Seq 32-m (Ex. 106)

Guide strand P1 was also duplexed with passenger strand F6-Seq 32 in amanner identical to that detailed above in Example 105 to provide duplexP2-Seq 32-m:

Scheme 28 is shown in FIG. 28-1 to FIG. 28-2.

Section Q. 3′ Enzymatically Cleaved Linker Bis Peptides Examples 107-109

Scheme 29 is shown in FIG. 29A-1 to FIG. 29C-2.

Synthesis of Q1 (Ex. 107)

In a Falcon tube, L6 (13.82 mg, 0.016 mmol) was dissolved in DMSO (1963μl) and cooled to 10° C. in an ice-bath. In a separate Falcon tube, B4(76.2 mg, 8.18 μmol) was dissolved in pH 8.3 NaHCO₃ 200 mM (1309 μl).The RNA solution was added to the DMSO solution and the reaction wasdetermined complete after 5 min.

The reaction was purified by ion-pairing chromatography (GX-281, XBridgePrep Phenyl 5 um, OBD, 30×150 mm, 30 mL/min, 5-45% of 100 mM TEAA inwater/100 mM TEAA in ACN, 20 min gradient). The resulting fractions weredialyzed against water 3× on Millipore 3K, 15 mL tubes, (4200 rpm, 4°C.) and then lyophilized to afford a white solid. Expected mass:10052.834. Found mass: 10051.0.

Synthesis of Q2-Seq 74 (Ex. 108)

See Synthesis of B10-Seq74 for reaction procedure. Q2-Seq 74—Found mass:13940.012.

Synthesis of Q3-Seq 74-b (Ex. 109)

See Synthesis of B11-Seq74 for reaction procedure. Q3-Seq 74-b—Foundmass: 20792.

Section R. 5′,3′ Di-Lipopeptide Conjugates

Examples 110-112

Scheme 30 is shown in FIG. 30A to FIG. 30E-3.

Synthesis of R² (Ex. 110)

L6 (23.2 mg) was dissolved in formamide (300 μl) and DMSO (300 μl), thenadded R¹ (50 mg) dissolved in pH 8.3 200 mM NaHCO₃ aqueous solution (600μl). After 5 min, precipitation appeared. Additional DMSO (300 μl) wasadded, whereupon most of solids redissolved. After a 15 min incubation,the reaction was purified using an XBridge Prep Phenyl column (5 uM,30×150 mm) using a gradient of 5-45% CH₃CN (100 mM TEAA)/water (100 mMTEAA), 20 min at 20 mL/min, collecting at 260 nm. The product fractionswere diluted with water to reduce the CH₃CN content to below 20% andcentrifugal dialyzed four times against water over a 3K membrane. Theretentate was frozen and lyophilized to a white solid.

Synthesis of R3 (Ex. 111)

Dissolved R2 in 500 ul of water, dissolved Compound 35 of SCHEME 38separately in 500 ul of water, then added GS solution to PS solution,vortexed thoroughly at RT, then checked analytical SAX HPLC confirmingthe formation of duplex. The solution was freeze dried to afford theduplex as a white amorphous solid.

Synthesis of R4-Seq 27-1 (Ex. 112)

Dissolved siRNA R3 in 2,2,2-trifluoroethanol containing 50 mM aceticacid (500 uL). Dissolved peptide in 2,2,2-trifluoroethanol containing 50mM acetic acid (500 uL), then added 8 M aqueous guanidiniumhydrochloride (30 uL). The siRNA solution was added to the peptidesolution to give a clear solution. After 1 h, the reaction mix wasdiluted with formamide (1 mL) and was purified on neutral SAX system(Buffer A: 1:1 water:TFE 20 mM MES pH 5.5 Buffer B: 1:1 water: TFE 20 mMMES pH 5.5 1M CsCl) in two runs. The product fractions were diluted withwater to reduce the TFE content to below 50% and dialyzed three timesagainst water over a 3K membrane. The retentate was frozen andlyophilized to a white solid.

Additional Synthesis of R3 Peptide Conjugates and R4 Duplexes.

Additional R3 conjugates of peptide sequences and the corresponding R4duplexes were prepared in a manner analogous to that detailed above.

Section S. Preparation of Alternative TetraGalNAc Ligands Examples113-115 Synthesis of TetraGalNAc Ligand Compounds 17a, 17b and 17c

The following Scheme 31 was used to prepare TetraGalNAc Compounds 17a,17b and 17c.

Synthesis of Compound 13

To a solution of 5-chloro-1-pentanol (3.0 g, 24.47 mmol) Compound 11 inDMF (20 mL) was added sodium azide (1.909 g, 29.4 mmol) Compound 12.After being stirred at 60° C. for overnight, the reaction mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography (EtOAc/Hexane 1:3), to give product Compound 13 as clearliquid. ¹H NMR (500 MHz, CDCl₃) δ 3.62 (m, 2H), 3.25 (t, J=6.9 Hz, 2H),1.63-1.53 (m, 4H), 1.45-1.40 (m, 2H).

Synthesis of Compound 15

Compound 13 (0.796 g, 6.16 mmol) and D-galactosamine pentaacetate (2.00g, 5.14 mmol) Compound 14 were suspended in 20 mL DCM, followed byaddition of trifluoromethanesulfonic acid (0.154 g, 1.027 mmol). Theresulting mixture was brought to reflux for overnight. LC-MS indicatedcompleted conversion of SM, the reaction mixture was diluted with EtOAcand washed with sodium bicarbonate and dried over sodium sulfate.Solvent was removed and the residue was purified by ISCO DCM/MeOH from100/0 to 90/10 over 30 min to afford Compound 15 as a white solid. ¹HNMR (500 MHz, CDCl₃) δ: 1.97 (6H, s), 2.02 (6H, s), 2.06 (6H, s), 2.15(6H, s), 3.28 (6H, t, J=6.89 Hz), 3.50 (3H, dt, J=9.63, 6.66 Hz), 3.68(1H, q, J=5.98 Hz), 3.94-3.92 (7H, m), 4.16-4.15 (5H, m), 4.73 (2H, d,J=8.34 Hz), 5.31 (2H, dd, J=11.16, 3.48 Hz), 5.40-5.38 (5H, m).Calculated mass: [M+H]⁺: C₁₉H₃₁N₄O₉, 459.2; observed: 459.4.

Synthesis of Compound 16.

Lys-alkyne Compound A1 (130 mg, 0.436 mmol) and GalNAc Azide 6 (999 mg,2.178 mmol) were dissolved in THE (5 mL, degassed). Copper (I)bromide-dimethyl sulfide complex (17.91 mg, 0.087 mmol) was added in oneportion to the reaction mixture and the THF solution was stirred forovernight at 40° C. The reaction color changed to blue/green, indicatingCu²⁺, fresh sodium ascorbate 37 mg in 0.2 mL of water was added toreaction mixture and allowed to react overnight. The reaction wasconcentrated and purified by RP HPLC 5-60 MeCN(0.5% TFA)/Water (0.5%TFA) over 20 min. The collected fractions were combined and lyophilizedto afford Compound 8 as a white solid. Calculated mass: [M+3H]³⁺:C₉₄H₁₄₅N₁₈O₃₈, 2134.0, m/z=711.3; observed: 711.9.

Synthesis of Compound 17a (Ex. 113)

To protected TetraGalNAc Compound 8 (300 mg, 0.141 mmol) in DCM/MeOH=1/15 mL at 0° C. was added Sodium Methoxide (91 mg, 1.688 mmol). Thereaction was stirred for 1 h and quenched by addition of 2 mL of water.Volatile solvent was removed, and the reaction mixture was purified byP4 bio gel with water and the collect fractions were combined andlyophilized to afford Compound 9 as a white solid. Calculated mass:[M+3H]³⁺: C₇₀H₁₂₁N₁₈O₂₆, 1629.9, m/z=543.3; observed: 543.8; [M+2H]²⁺:C₇₀H₁₂₁N₁₈O₂₆, 1628.9, m/z=814.5; observed: 814.9.

Synthesis of Compounds 17b and 17c (Ex. 114 and Ex. 115)

Syntheses of Compounds 17b and 17c which have the following structureswere accomplished in a manner similar to that used for Compound 17ausing the appropriate azide source.

Example 116 Scheme of Conjugation of TetraGalNAc Ligands

Scheme 32 as shown in FIG. 31A and FIG. 31B shows a general scheme thatcan be used to prepare tetraGalNAc-siRNA conjugates.

Using the general scheme 32, Conjugates 10-1, 10-2, 10-3, 10a-1, 17a-1,17b-1, 17c-1 can be obtained. The coupling procedure can be performed ona preformed siRNA duplex or on a single strand followed by annealing.Alternatively, one can utilize the protocol outlined in Bioconjug Chem.2011, 22, pp. 1723-8.

Example 117

Synthesis of TetraGalNAc-siRNA Conjugate (A11-a) via TetraGalNAc AcetateCompound A9 To a solution of tetraGalNAc acetate (A9, 58.7 mg, 0.027mmol) in acetonitrile (1.5 ml) was added DIPEA (2.2 mg, 0.055 mmol) andHATU (10.44 mg, 0.027 mmol). The mixture was stirred at room temperaturefor 30 min, transferred into a solution siRNA (0.014 mmol) in water (1.5ml) and acetonitrile (1.5 ml) via a syringe pump over 20 min, andstirred for 30 min before it was concentrated under vacuum down to 1.5mL. Sodium carbonate (218 mg, 2.059 mmol) was then added, followed byMeOH (0.50 ml). The resulted solution was stirred at room temperaturefor 16 h, concentrated, purified via dialysis, and lyophilized to yieldConjugate A11-a.

The coupling protocol described for A11-a can also be performed with A10instead of A9.

Examples 118-119 Synthesis of Conjugates A11-b and A11-c (Ex. 118 andEx. 119)

A similar protocol was used for Conjugates A11-b and A11-c. Duplexformation with the appropriate antisense or sense strand can beperformed using the protocol described for B11.

Example 120 Synthesis of 3′5′ Bis TetraGalNAc-siRNA Conjugate SingleStrand 18

To a solution of tetraGalNAc acid Compound 10 (41.2 mg, 0.025 mmol) inDMSO (200 uL) was added HATU (9.6 mg, 0.025 mmol) and DIPEA (17.6 uL,0.126 mmol). The mixture was stirred at room temperature for 15 min,transferred into a solution of diamino-siRNA (18.8 mg, 2.52 umol) inwater (40 uL) and DMSO (360 uL) and stirred for 30 min. The mixture wasdiluted with water (1.5 mL) and purified on a XBridge Prep Phenyl column(5 uM, 19×250 mm) using a gradient of 0-30% CH₃CN/water containing 100mM TEAA. The fractions were concentrated via dialysis and lyophilized toyield Compound 18.

Example 121 Synthesis of 3′5′ Bis TetraGalNAc-siRNA Duplex Conjugate19-1 (Ex. 121)

Scheme 33 as shown in FIG. 32A and FIG. 32B was used to prepareTetraGalNAc-siRNA Conjugate 19-1.

A solution of 3′5′ bis tetraGalNAc-siRNA conjugate 18 (13.7 mg, 1.29umol) in water (200 uL) was added to a solution of Guide siRNA (9.3 mg,1.35 umol) dissolved in water (100 uL) and heated at 90 C for 1 minute.The resulting solution was cooled and lyophilized to yield duplex 19-1.

Example 122 Synthesis of TetraGalNAc Ligand Compound 24 (Ex. 122)

The following Scheme 34 was used to prepare tetraGalNAc ligand Compound24.

Synthesis of Compound 22

To a solution of N-BOC-1,3-DAMINOPROPANE (Compound 20, 115 mg, 0.660mmol) in 1:1 CH₂Cl₂/CH₃CN (1 mL) at 0° C. was added a solution of3-maleimidopropionic acid N-hydroxysuccinimide ester (Compound 21, 185mg, 0.695 mmol) dissolved in acetonitrile (4 mL) and CH₂Cl₂ (1 mL). Themixture was stirred for 1 h and concentrated in vacuo. The residue waspurified by silica gel chromatography (0-50 MeOH/CH₂Cl₂ to give productCompound 22. Calculated mass: [M+H]⁺: C₁₅H₂₄N₃O₅, 326.2; observed:326.3.

Synthesis of Compound 23

To a solution of maleimide Compound 22 (56 mg, 0.172 mmol) in CH₂Cl₂ (1ml) was added a solution of 4M HCl (1 ml, 4.00 mmol) in dioxane. Themixture was stirred for 1 h and concentrated in vacuo. The residue wasazeotroped with CH₂Cl₂ (2×) and dried under vacuum to give productCompound 23. Calculated mass: [M+H]⁺: C₁₀H₁₆N₃O₃, 226.1; observed:226.3.

Synthesis of tetraGalNAc Maleimide Compound 24 (Ex. 122)

To a solution of tetraGalNAc acid Compound 10 (100 mg, 0.061 mmol) inDMF (500 uL) was added HATU (34.9 mg, 0.092 mmol), Et₃N (42.6 uL, 0.306mmol) andN-(3-aminopropyl)-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamidehydrochloride (16.0 mg, 0.061 mmol). The mixture was stirred at roomtemperature for 1.5 h, acidified with TFA and purified by reverse phase0-50% CH₃CN/water containing 0.1% TFA. The fractions were lyophilized toyield Compound 24. Calculated mass: [M+2H]²⁺: C₇₆H₁₂₅N₂₁O₃₂, 1843.8, mz=921.9; observed: 922.7.

Example 123 Synthesis of Compound 26

Scheme 35 as shown in FIG. 33A and FIG. 33B was used to prepare Compound26.

To a degassed solution of 2′-3,17 propargyl siRNA (RNA 25, 33 mg, 4.49umol) and PEG9 SPDP azide (26 mg, 36 umol, prepared from commercialPEG-azide and pyridyl disulfide reagents) in 3:1 DMA/water (1 mL) wasadded a degassed solution of Copper (I) Bromide-Dimethylsulfide Complex(1.8 mg, 9.0 umol). The mixture was stirred for 72 h at roomtemperature, diluted with water (2 mL), filtered using a 0.45 uM syringefilter and concentrated by dialysis. The concentrated mixture waspurified on a XBridge Prep Phenyl column (5 uM, 19×250 mm) using agradient of 0-50% CH₃CN/water containing 100 mM TEAA. The fractions wereconcentrated via dialysis and lyophilized to yield Compound 26.

Examples 124-125 Synthesis of Compounds 27 and 28 (Exs. 124-125)

Scheme 36 as shown in FIG. 34A to FIG. 34C was used to prepare Compounds27 and 28.

Synthesis of Compound 27 (Ex. 124)

To a solution of 2′-3,17 click PEG9 SPDP Conjugate 26 (13.2 mg, 1.50μmol) in water (1 mL) was added a solution of TCEP hydrochloride (9.15mg, 32.2 umol) dissolved in water (0.5 mL). The mixture was stirred atRT for 30 min then purified on a XBridge Prep Phenyl column (5 uM,19×250 mm) using a gradient of 5-40% CH₃CN/water containing 100 mM TEAA.The fractions were concentrated via dialysis and lyophilized to yieldCompound 27.

Synthesis of Compound 28 (Ex.125)

To a solution of 2′-3,17-click PEG9SH 27 (3 mg, 0.35 μmol) in pH 6.0acetate buffer (100 uL) was added a solution of tetra GalNAc maleimide(5.1 mg, 2.77 μmol) dissolved in pH 6.0 acetate buffer (100 uL). Themixture was stirred at room temperature for 30 min then purified on aXBridge Prep Phenyl column (5 uM, 19×250 mm) using a gradient of 5-40%CH₃CN/water containing 100 mM TEAA. The fractions were concentrated viadialysis and lyophilized to yield Compound 28.

Example 126 Synthesis of 2′-3,17 Bis TetraGalNAc-siRNA Duplex Conjugate29

The procedure detailed for Conjugate 19 was used to duplex 28 to makeConjugate 29.

Example 127 Synthesis of TetraGalNAc Thiol Compound 31

Scheme 37 below was used to prepare Compound 31.

To a solution of tetraGalNAc acid Compound 10 (54 mg, 0.033 mmol) inN,N-dimethylacetamide (500 μl), was added crystamine dihydrochloride 30(14.9 mg, 0.066 mmol), EDC (12.7 mg, 0.066 mmol), HOAT (10.2 mg, 0.066mmol) and DIPEA (57.7 μl, 0.330 mmol). The mixture was stirred at roomtemperature for 18 h, then added a solution of DTT (50.9 mg, 0.330 mmol)in N,N-dimethylacetamide (100 μl). The mixture was stirred at roomtemperature for 0.5 h, acidified with TFA and purified by reverse phase0-30% CH₃CN/water containing 0.1% TFA. The fractions were lyophilized toyield Compound 31. Calculated mass: [M+2H]²⁺: C₆₈H₁₁₅N₁₉O₂₉S, 1695.8,m/z=847.9; observed: 848.0.

Examples 128-130 Synthesis of Conjugates 35-37

Scheme 38 as shown in FIG. 35A and FIG. 35B was used to prepareConjugates 35-37.

Synthesis of Compound 33

To a degassed solution of 2′-click 15 GS Compound 32 (130 mg, 0.019mmol) and (9H-fluoren-9-yl)methyl (2-azidoethyl)carbamate (29.1 mg,0.095 mmol) in 3:1 DMA/water (2 mL) was added a solution of Copper (I)bromide-dimethylsulfide Complex (9.72 mg, 0.042 mmol) dissolved indegassed DMSO (0.32 mL). The mixture was stirred at 45° C. for 2 h,cooled to room temperature, and added pH 8 EDTA (0.5 M, 2 mL) to quenchreaction. Stirred for 15 min and purified on a XBridge Prep Phenylcolumn (5 uM, 30×150 mm) using a gradient of 0-45% CH₃CN/watercontaining 100 mM TEAA. The fractions were concentrated via dialysis. Tothe combined material in water (3 mL) was added a solution of piperidine(936 μL, 1.891 mmol). The mixture was stored at 4° C. for 18 h, dilutedwith water (10 mL) and filtered off solids through syringe filter. AddedpH 8 EDTA (0.5 M, 2 mL), concentrated via dialysis and lyophilized toyield Compound 33.

Synthesis of Compound 34

To a solution of 2′-15 click C2 NH2 GS Compound 33 (43.6 mg, 6.26 μmol)in 200 mM NaHCO₃soln (2000 μl) and formamide (1000 uL) was added asolution of N-Succinimidyl-3-[2-pyridyldithio]propionate (17.9 mg, 0.057mmol) dissolved in DMSO (298 uL). The mixture was stirred at 10° C. for15 min, diluted with water (10 mL) and Formamide (1 mL), andconcentrated by dialysis. Added 2M TEAA (200 uL) and purified on aXBridge Prep Phenyl column (5 uM, 19×250 mm) using a gradient of 5-40%CH₃CN/water containing 100 mM TEAA. The fractions were concentrated viadialysis and lyophilized to yield Compound 34.

Synthesis of 2′-15 TetraGalNAc-siRNA Conjugate 35 (Ex. 128)

To a solution of 2′-15 click C2 NH2 NHS SPDP GS Compound 34 (13 mg, 1.82μmol) in 1:1 formamide/water (200 μl) was added a solution oftetraGalNAc SH (4.62 mg, 2.72 μmol) in formamide (200 uL). The mixturewas stirred at room temperature for 3.5 h, added 2M TEAA (50 uL) andpurified on a XBridge Prep Phenyl column (5 uM, 19×250 mm) using agradient of 2-35% CH₃CN/water containing 100 mM TEAA. The fractions wereconcentrated via dialysis and lyophilized. The resulting solid waspurified on a Proteomix SAX-NP10 column (22.1×50 mm) using a gradient of2-30% (Solvent A: 60:40 TFE/water with 40 mM Et3N, Solvent B: 60:40TFE/water with 40 mM Et3N, 1M Guanidine HCl). The fractions wereconcentrated via dialysis and lyophilized to yield Conjugate 35.

Synthesis of Conjugates 36 and 37 (Ex. 129 and Ex. 130)

The procedure detailed for Conjugate 19-1 was used to duplex Conjugate35 and the appropriate passenger strand to prepare Conjugates 36 and 37,respectively.

Examples 131-139 Synthesis of Conjugates 38-45 (Exs. 131-139)

Scheme 39 as shown in FIG. 36A to FIG. 36C, was used to prepareConjugates 38-44.

Scheme 40. Examples of different linkers from Table 2 as shown in FIG.37, used to conjugate tetraGalNAc to siRNA.

Step 1: Passenger-RNA and Linker, Example with Proline to IllustrateProtocol

To a solution of FMOC-PRO-OH (11.11 mg, 0.033 μmol) in 120 μL DMSO wereadded DIPEA (43.2 μl, 0.247 μmol) followed by HATU (10.96 mg, 0.029μmol). The mixture, slightly yellow, was stirred at room temperature for30 min. The mixture was then added to a solution of the oligonucleotidepassenger strand TEAA salt (60 mg, 8.24 μmol) in 500 μL of (10%H2O/DMSO), and the mixture continued to stir at room temperature for onehour. The reaction mixture showed desired product via LC-MS. To thereaction mixture was added diethylamine (43.0 μl, 0.412 μmol) and themixture was stirred for one hour, confirmed desired product via LC-MS.The reaction mixture was purified by centrifugal dialysis using 3 kDacut-off membrane. The process was repeated three times with water (14 mLeach time). The resulting solution was concentrated, frozen, andlyophilized overnight to yield product as a white fluffy solid. LC/MSconfirms product [7384.9].

Step 2: TetraGalNAc-Linker-Passenger RNA

To a solution of TetraGalNAc Compound 10 (53.2 mg, 0.033 μmol) in 532 μLDMSO were added DIPEA (42.6 μl, 0.244 μmol) followed by HATU (12.36 mg,0.033 μmol). The mixture, slightly yellow, was stirred at RT for 30 min.The mixture was then added to a solution of the linker-oligonucleotidepassenger strand in 500 μL of DMSO, and the mixture continued to stir atroom temperature for two hours. LC/MS showed desired product. Thereaction mixture was subjected to centrifugal dialysis using 3 kDacut-off membrane. The process was repeated three times with water (14 mLeach time). The resulting solution was purified by Gilson PLC 2020 usingXBRIDGE PHENYL, 10-27% CH₃CN with 200 μM TEAA for 35 minutes. Collectionsolution was concentrated via centrifugal dialysis using 3 kDa cut-offmembrane. The resulting concentrated solution was treated with 1.0N NaCland centrifugal dialysis. The process was repeated five times with water(14 mL each time). The resulting concentrated solution (˜1.5 mL) wasfrozen and lyophilized overnight to yield product as a white fluffysolid. LC/MS confirms product [9002.5].

Step 3: Duplex Formation

To a TetraGalNAc-linker-RNA (18.5 mg, 2.055 μmol) in 1.5 mL of water wasduplexed with ApoB guide strand (14.12 mg, 2.055 μmol) in 1.5 mL ofwater. The mixture was heated at 90° C. for 5 min with stir bar. Theduplex was cooled and stir bar removed. The solution was lyophilizedover two days to yield desired duplex Conjugate 38 as a white fluffysolid. LC/MS confirms product [16048].

ALL the remaining conjugates were prepared using the same generalprocedure.

Examples 140-142 Synthesis of Compounds/Conjugates 46-48

Scheme 41 as shown in FIG. 38A to FIG. 38E was used to prepare Compoundsand/or Conjugates 46-48.

Synthesis of RNA Compound 46 (Ex. 140)

SPDP Acid (2.2 mg, 10.3 μmol) was dissolved DMSO 100 μL andN,N-diisopropylethylamine (14.0 μl, 0.08 mmol), HATU (19.6 mg, 0.051mmol) were added sequentially. RNA (15 mg, 2.06 μmol) in 200 μL ofDMSO:Water (9:1) was added and the resulting reaction mixture wasstirred for 1 h, reaction was quenched by addition of 3 mL water anddialyzed down to 500 μL, diluted by formamide to 3 mL and purified bySAX (Buffer A: 60% TFE in water, 20 mM TEA, Buffer B: 60% TFE in water,20 mM TEA, 1 M CsCl, gradient A/B from 100/0 to 35/65 over 15 min). Thecollected fractions were combined and dialyzed against water andlyophilized to afford Compound 46 as a white solid. Calculated mass:[M−H]⁻: C₂₃₄H₃₀₀F₈N₇₂O₁₅₀P₂₃S3, 7480.1; observed: 7483.0.

Synthesis of Conjugate 47 (Ex. 141)

RNA Compound 46 (22 mg, 2.9 μmol) and tetraGalNAc Thiol Compound 31(10.0 mg, 5.9 μmol) were dissolved in formamide:pH=6.8 Tris buffer (3:1)400 μL and stirred for 1 h. The reaction mixture was purified by SAX(Buffer A: 60% TFE in water, 20 mM TEA, Buffer B: 60% TFE in water, 20mM TEA, 1 M CsCl, gradient A/B from 100/0 to 35/65 over 15 min). Thecollected fractions were combined and dialyzed against water andlyophilized to afford Conjugate 47 as a white solid. Calculated mass:[M−H]⁻: C₂₉₇H₄₁₀F₈N₉₀O₁₇₉P₂₃S3, 9063.9; observed: 9066.2.

Synthesis of Conjugate 48 (Ex. 142)

Conjugate 47 (10.9 mg, 1.20 μmol) and guide strand (7.81 mg, 1.14 μmol)were mixed in RNAse free water 1 mL for 2 h. The reaction mixture waslyophilized to afford duplex Conjugate 48 in quantitative yield.

Examples 143-145 Synthesis of Compounds/Conjugates 49-51

Scheme 42 as shown in FIG. 39A to FIG. 39C was used to prepare Compoundsand/or Conjugates 49-51.

Synthesis of RNA Compound 49 (Ex. 143)

33.3 mg of siRNA passenger strand was weighed into a 4 mL vial then 1 mL100 mM NaHCO₃ was added to dissolve. Added 0.86 uL of propionicanhydride and let stir at RT. After aging ˜2 h, spin dialyzed 3× againstwater. Filtered through frit and the solution was dried vialyophilization to afford RNA Compound 49.

Synthesis of Conjugate 50 (Ex. 144)

Step 1. Charge 2.8 mg azide, 25.7 mg siRNA, 25 ml N2 sparged DMSO and 4ml water to 40 mL vial. Sparge with N₂. Charge 2.98 mL of Cu/ligandsolution (N₂ sparged, 20/100 umol in 10 ml DMSO). Agitate at RT undersparged N₂.

Step 2. Charge Compound 10 and 1 ml DMSO. Charge 6 uL of DIPEA andagitate for 2 min. Charge 6 mg HBTU and agitate for 2 min. Charge siRNAmixture from Step 1. The reaction was not complete so repeated with halfof previous reagent charge. Evaporated the reaction mixture, dialyzedand HPLC purified (X-Bridge Phenyl, TEAA/ACN gradient). Evaporated,dialyze and lyophilized to afford Conjugate 50.

Synthesis of Conjugate 51 (Ex. 145)

Dissolve GS (Conjugate 50) 10.65 mg in 1 ml water and dissolve PS(Conjugate 49) 10.20 mg in 1.17 ml water. Added 8.7 mg of Conjugate 49to all of Conjugate 50 to form a 1:1 duplex. Heat to 90° C. for 1 min,cool to RT over 15 min. The solution was filtered and dried vialyophilization to afford Conjugate 51 as a white solid.

RNA Silencing Activity of Compounds Transfected with Lipofectamine inLuciferase Constructs

HEK293 cells stably transfected with luciferase vector that containstarget sites for siRNA in 3′UTR of renilla luciferase were generated.These cells were seeded on 96-well tissue culture plates (Corning:#3903) at a density of 7.5e3 cells per well in DMEM 10% serum media.Cellular plates were then incubated at 37° C./5% CO2 for 24 hr. Afterincubation, plates were treated with test compounds co-transfected withtransfection reagent Lipofectamine 2000 (invitrogen: #11668-019) inOpti-MEM (Gibco: #31985) in accordance to manufacturers protocol. Thetreatment concentrations ranged from 10 nM to 0.03 μM. Treated plateswere then incubated for 24 hr at 37° C./5% CO2. Following treatmentincubation, cells were lysed and processed in accordance to Dual-Glo™Luciferase Assay (Promega: E2920) and read on a TECAN safire2 platereader.

RNA Silencing Activity of Compounds Transfected with Lipofectamine inHepG2 Cells

HepG2 cells (ATCC: HB-8065) were seeded on collagen coated plates(BioCoat: 356649) at a density of 7.5e3 cells per well in DMEM 10% serummedia. Cellular plates were then incubated at 37° C./5% CO2 for 24 hr.After incubation, plates were treated with test compounds co-transfectedwith transfection reagent Lipofectamine 2000 (invitrogen: 11668-019) inOpti-MEM (Gibco: 31985) in accordance to invitrogen protocol. Thetreatment concentrations ranged from 10 nM to 0.03 μM. Treated plateswere then incubated for 24 hr at 37° C./5% CO2. Following treatmentincubation, cells were lysed with PLA Buffer (AB: 4448542) in accordanceto supplied protocol. Resulting cell lysate was reverse transcribed tocDNA using High Capacity cDNA Kit (AB: 4368813) and run through qPCRusing Life Technology 7900.

In vivo Evaluation of RNAi Activity

CD1 female mice were dosed by subcutaneous injection in 200 ul volume.Animals were observed for behavioral or physiological changes. Animalswere sacrificed 72 hrs post dose by C02 asphyxiation followed byexsanguination via cardiac puncture. The liver samples were as 3 mmpunches from the medial lobe and put into RNAlater tubes for isolationof total RNA. The mRNA knockdown analysis was conducted by Tagmananalysis using standard procedures.

Scheme 43. General Description for Illustrative Purposes of NomenclatureUsed in Table 6 as shown in FIG. 40. Exact siRNA sequences used in Table6 can be found in Table 5.

A summary of in vitro and in vivo data of selected Compounds/Conjugatesis shown in Table 6 and Table 7.

TABLE 6 In vitro and In Vivo Activity for Compounds Described in SectionB-D. RBC Hemolysis Data on Free Peptide EC 50 pH7.4 EC 50 pH5.5 % KD 2.5mpk % KD 5 mpk % KD 2.5 mpk Compound # (uM) (uM) (SC admin) (iv admin)(iv admin) B8-seq137-b 8.3 4.3 47 B8-seq470-b 8.5 3.8 57B8-seq1678-b >20 5 49 B8-seq 92-b 0.3 0.3 57 B8-seq1677-b 10 0.4 57B8-seq-463-b 18 9.8 61 B8-seq1675-b 7 4.5 47 B11-seq1-b 5.3 0.7 49B11-seq2-b >10 1.2 32 B11-seq3-b >10 0.5 49 B11-seq4-b 4.3 0.2 55B11-seq5-b 5 0.5 74 B11-seq6-b >10 1 53 B11-seq7-b >10 0.7 45 B11-seq8-b22 B11-seq9-b 8.9 1.7 28 B11-seq10-b 6 1.8 35 B11-seq11-b 0.39 0.04 21B11-seq12-b 2 0.2 45 B11-seq13-b 1.9 0.2 5 64 B11-seq14-b 2.27 1.61 26B11-seq15-b >10 0.4 28 B11-seq16-b 2.8 0.6 26 B11-seq17-b 4.4 0.7 34B11-seq18-b 1 0.4 61 B11-seq19-b >10 0.7 64 B11-seq20-b 3.7 2.05 63B11-seq21-b 2.2 0.4 56 B11-seq22-b 6 0.5 33 B11-seq23-b 7.3 6.1 59B11-seq24-b >10 0.2 58 B11-seq25-b >10 3.6 52 B11-seq26-b 4.6 1.4 38 6557 B11-seq27-b >10 0.4 61 B11-seq28-b 0.7 0.1 25 B11-seq29-b >10 2 20B11-seq30-b >10 1.5 29 B11-seq31-b 1.5 0.3 64 B11-seq32-b 4.5 1.4 58B11-seq33-b 0.02 0.04 35 B11-seq34-b 0.12 0.05 30 B11-seq35-b 0.03 0.0337 B11-seq36-b 7.5 2.5 53 B11-seq37-b 6 2 22 B11-seq38-b 0.95 0.44 61B11-seq39-b 1 0.6 58 B11-seq40-b 0.2 0.2 63 B11-seq41-b >10 0.7 36 27B11-seq42-b 1.3 1.9 41 57 B11-seq43-b 0.9 0.3 55 B11-seq44-b 2.1 1.4 3356 B11-seq45-b >10 0.07 51 53 B11-seq46-b 1.1 0.04 56 46 B11-seq47-b >100.4 49 51 B11-seq48-b 3.1 1.5 47 61 B11-seq49-b 4 0.6 37 49B11-seq50-b >10 1.9 10 43 B11-seq51-b 11 48 B11-seq52-b >10 6.4 14 59B11-seq53-b 1.17 0.37 45 B11-seq54-b 0.89 0.38 49 B11-seq55-b 0.51 0.18−7 47 B11-seq56-b 1.46 0.19 12 48 B11-seq57-b 3.5 0.59 −11 B11-seq58-b14.47 0.31 18 B11-seq59-b >20 0.65 7 52 B11-seq60-b 19.57 0.38 39B11-seq61-b 1.39 0.65 55 B11-seq62-b >20 5.86 52 B11-seq63-b 0.94 0.6437 B11-seq64-b >20 1.8 41 B11-seq65-b 1.38 1.87 28 B11-seq66-b >20 0.8254 B11-seq67-b >20 0.87 39 B11-seq68-b >20 5.05 56 B11-seq69-b >20 0.9134 B11-seq70-b 3.68 1.86 32 B11-seq71-b >20 3.56 44 B11-seq72-b 10.632.54 39 B11-seq73-b >20 4.2 38 B11-seq74-b 12.68 4.34 60 B11-seq75-b >100.9 55 B11-seq76-b 6.4 1.7 3 53 B11-seq77-b 0.17 0.23 38 B11-seq78-b 0.20.33 47 B11-seq79-b 1.52 1.86 47 B11-seq80-b >20 6.24 56 B11-seq81-b >203.91 51 B11-seq82-b 17 1.79 40 B11-seq83-b >20 6.19 35 B11-seq84-b 0.70.15 44 B11-seq85-b >10 0.1 45 B11-seq86-b >20 17.81 27 B11-seq87-b >100.02 30 B11-seq88-b 2.35 0.07 56 B11-seq89-b 3.29 0.14 51B11-seq90-b >10 0.5 42 B11-seq91-b 26 B11-seq92-b 59 B11-seq93-b >205.88 51 B11-seq94-b 5.2 1.61 46 B11-seq95-b 3.59 3.1 43 B11-seq96-b16.08 4.9 55 B11-seq97-b >20 5.56 52 B11-seq98-b >20 3.37 40 B11-seq99-b12.9 5.61 43 B11-seq100-b 10.24 3.45 43 B11-seq101-b >20 4.85 46B11-seq102-b >20 4.87 54 B11-seq103-b >20 3.86 43 B11-seq104-b 6.72 3.2656 B11-seq105-b >10 >10 30 B11-seq106-b 8.4 0.24 34 B11-seq107-b 10.413.52 41 B11-seq108-b 5.6 2.69 40 B11-seq109-b >20 5.78 36B11-seq110-b >20 3.36 43 B11-seq111-b >20 0.26 36 B11-seq371-b >20 2.845 B11-seq-1675-b 14.2 3.5 53 B13-seq1676-b 14.2 3.5 53 B8-seq32-c 4.51.4 C6-seq-31c 1.5 0.3 31 C6-seq32-c 4.5 1.4 36 C6-seq106-c 7 0.7 30C12-seq32-c 4.5 1.4 68 C15-seq32-c 4.5 1.4 39 D7-seq32-d 4.5 1.4 52E10-seq137-b >20 3.3 F6-seq 26-f >20 >20 47 F6-seq32-f 4.5 1.4 47F6-seq463-f 18 9.8 60 F6-seq491-f >20 3.3 72 F6-seq492-f >20 6.3 66F6-seq-612-f 19 6 59 F6-seq1693-f 17.1 0.6 38 F6-seq1694-f 15.6 4.4 43G5-seq463-g 18 9.8 47 G5-seq489-g >20 >20 48 H7-seq8-h 20 1.3 13 25H7-seq26-h 4.6 1.4 35 H7-seq32-h 4.5 1.4 20 30 H7-seq37-h 6 2 39H10-seq26-h 4.6 1.4 20 H10-seq32-h 4.5 1.4 33 I10-seq-1680-f >20 1.6 67110-seq-1681-f >20 1.4 66 I10-seq-1682-f >20 1.6 66 K6-seq37-h 6 2 55K6-seq-74-h 12.7 4.3 48 K6-seq463-h 18 9.8 55 L11-seq463j 18 9.8 52M4-seq463-j 18 9.8 52 N4-seq106-k 7 0.7 69 N4-seq197-k >20 >20 63N4-seq283-k >20 >20 64 O3-seq-463-k 18 9.8 35 70 P2-seq32-k 4.5 1.4 61P2-seq32-m 4.5 1.4 64 Q3-seq32-b 4.5 1.4 45 Q3-seq74-b 12.7 4.3 43Q3-seq1675-b 14.2 3.5 70 R4-seq1690-1 1.9 0.6 79 R4-seq1691-1 1.6 0.5 55R4-seq1692-1 >20 >20 72 R4seq1695-1 14.2 0.3 79 R4-seq1696-1 >20 >20 36

TABLE 7 In vitro and In Vivo Activity for Compounds Generated in SectionE. (Starting siRNA sequence information can be found in Table 8). Dose(mpk) IC50 w/LF2K Starting siRNA Route of In vivo in HEK- ASGR bindingEntry Compound sequence code Administration % KD (72 h) Luc [pM] IC50 nM1 10a-1 51 5, 15 SC 33.6; 69.5 15.44 36.7 2 10b-1 54 SC 5, 15; IV 15 42,49, 13 19.64 18.1 3 10-2 56 5, 50 SC 40, 56 (24 h) 23.4 4 10-3 57 1,2.5, 5 SC 20, 45, 60 52 (HepG2) 5 17a-1 51 5 SC; 15 IV 11, 5 20.16 49.16 17b-1 54 5 SC; 15 IV 12, 22 43.96 33.3 7 19-1 52 5; 15 SC 32; 68 24.043.6 8 29 53 15 SC; 15 IV 43, 0 17.83 22 9 36 58 1, 2.5, 5 SC 16, 43, 5610 37 58 1, 2.5, 5 SC 16, 32, 40 11 38 51 5 SC, 15 IV 36, 33 71 17 12 3951 5 SC, 15 IV 19, 31 46.8 44 13 40 51 5, 15 SC 33, 62 76.8 77 14 41 515, 15 SC 28, 74 98.6 134 15 42 51 5, 15 SC 19, 73 309.7 135 16 43 51 5,15 SC 8, 73 64.8 45 17 44 51 5, 15 SC 31, 73 67.1 66 18 45 51 5 SC, 15IV 20, 4 73.4 11 19 48a-1 51 5, 15 SC 10.24; 59.93 23.43 20 48b-1 53 5,15 SC 19.87; 42.08 57.96 21 51 55 5; 15 40; 45 1838.47 94.8

TABLE 8Starting siRNA sequence information used to prepare conjugates from Table 7.Gene Duplex SEQ ID Entry Target Strand Sequence Code NO.: 1 ApoBPassenger [6amiL][iB][omeC][omeU][omeU][omeU][fluA][fluA][omeC] 51 1721[fluA][fluA][omeU][omeU][omeC][omeC][omeU][fluG][fluA][fluA][fluA][omeU][iB] ApoB Guide[rAs][rUs][rUs][omeU][omeC][fluA][fluG][fluG][fluA][fluA] 1722[omeU][omeU][fluG][fluU][omeU][fluA][fluA][fluA][fluG] [omeUs][omeU 2ApoB Passenger [6amiL][iB][omeC][omeU][omeU][omeU][fluA][fluA][omeC] 521723 [fluA][fluA][omeU][omeU][omeC][omeC][omeU][fluG][fluA][fluA][fluA][omeU][iB][6amiL] ApoB Guide[rAs][rUs][rUs][omeU][omeC][fluA][fluG][fluG][fluA][fluA] 1724[omeU][omeU][fluG][fluU][omeU][fluA][fluA][fluA][fluG] [omeUs][omeU] 3ApoB Passenger [6amiL][iB][omeC][omeU][clickU][omeU][fluA][fluA][omeC]53 1725 [fluA][fluA][omeU][omeU][omeC][omeC][omeU][fluG][fluA][clickA][fluA][omeU][iB][C6SH ApoB Guide[rAs][rUs][rUs][omeU][omeC][fluA][fluG][fluG][fluA][fluA] 1726[omeU][omeU][fluG][fluU][omeU][fluA][fluA][fluA][fluG] [omeUs][omeU] 4ApoB Passenger [iB][omeC][omeU][omeU][omeU][fluA][fluA][omeC][fluA] 541727 [fluA][omeU][omeU][omeC][omeC][omeU][fluG][fluA][fluA][fluA][omeU][iB][6amiL] ApoB Guide[rAs][rUs][rUs][omeU][omeC][fluA][fluG][fluG][fluA][fluA] 1728[omeU][omeU][fluG][fluU][omeU][fluA][fluA][fluA][fluG] [omeUs][omeU] 5ApoB Passenger [6amiL][iB][omeC][omeU][omeU][omeU][fluA][fluA][omeC] 551729 [fluA][fluA][omeU][omeU][omeC][omeC][omeU][fluG][fluA][fluA][fluA][omeU][iB] ApoB Guide[rAs][rUs][rUs][omeU][omeC][fluA][fluG][fluG][fluA][fluA] 1730[omeU][omeU][fluG][fluU][clickU][fluA][fluA][fluA][fluG] [omeUs][omeU] 6SSB Passenger [6amiL][iB][fluA][omeC][fluA][fluA][omeC][fluA][fluG] 561731 [fluA][omeC][omeU][omeU][omeU][fluA][fluA][omeU][fluG][omeU][fluA][fluA][dTs]dT[iB] SSB Guide[rUs][rUs][rAs][omeC][fluA][omeU][omeU][fluA][fluA][fluA] 1732[fluG][omeU][omeC][fluU][fluG][omeU][omeU][fluG] [omeU][omeUs][omeU] 7CTNNB1 Passenger [6amiL][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG]57 1733 [fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluG][clickA][fluA][fluA][omeUs][omeU][iB][C3SH] CTNNB1 Guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU] 1734[omeC][fluA][omeA][fluU][omeC][fluC][omeA][fluA][omeC][fluA][omeG][omeUs][omeU] 8 CTNNB1 Passenger[6amiL][iB][omeC][omeU][clickG][omeU][omeU][fluG][fluG] 58 1735[fluA][omeU][omeU][fluG][fluA][omeU][omeU][omeC][fluG][clickA][fluA][fluA][omeUs][omeU][iB][C3SH] CTNNB1 Guide[omeUs][fluUs][omeUs][fluC][omeG][fluA][omeA][fluU] 1736[omeC][fluA][omeA][fluU][omeC][fluC][clickA][fluA][omeC][fluA][omeG][omeUs][omeU]As used herein, ome=2′ methoxy; flu=2′ fluoro; click=2′ propagyl;iB=inverted abasic; “s” subscript=phosphorothioate; and r=2′ ribo;6amil=n-hexylamino; C3SH=n-propylthiol and C6SH=n-hexylthiol.

One skilled in the art would readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The methodsand compositions described herein, as presently representative ofpreferred embodiments, are exemplary and are not intended as limitationson the scope of the invention. Changes therein and other uses will occurto those skilled in the art, which are encompassed within the spirit ofthe invention, are defined by the scope of the claims.

We claim:
 1. A method of delivering an oligonucleotide to a cell of asubject in need, comprising: providing or obtaining a modularcomposition comprising: 1) a single stranded or double strandedoligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), (II)or (III), which may be the same or different:

wherein: X is —O—, —S—, —CR¹R²— or —NR¹—; R¹ and R² are eachindependently selected from the group consisting of hydrogen and C₁-C₆alkyl; n is 1, 2, 3, or 4; and the bond with “

” indicates the point of attachment of the tetraGalNAc ligands to theoligonucleotide; optionally, 3) one or more linkers, which may be thesame or different; optionally, 4) one or more peptides independentlyselected from SEQ ID No. 1-474, or the D-amino acid, retro-inverso, andcysteine conjugation point variants thereof, which may be the same ordifferent, wherein the cysteine conjugation point variants thereofrefers to variants of the peptides comprising a cysteine conjugation, ora cysteine or other thiol-containing moiety added to the C- orN-terminus of the peptides; and optionally, 5) one or more targetingligands, solubilizing agents, pharmacokinetics enhancing agents, lipids,and/or masking agents; and contacting the cell of the subject with themodular composition for a period of time sufficient for the cell tointernalize the modular composition.
 2. The method of claim 1, whereinthe modular composition comprises: 1) a single stranded or doublestranded siRNA; 2) 1-8 tetraGalNAc ligands of Formula (I), (II) or(III), which may be the same or different; 3) 1-24 linkers, which may bethe same or different; optionally, 4) 1-8 peptides independentlyselected from SEQ ID No. 1-474, or the D-amino acid, retro-inverso, andcysteine conjugation point variants thereof, which may be the same ordifferent; and optionally, 5) 1-8 targeting ligands, solubilizingagents, pharmacokinetics enhancing agents, lipids, and/or maskingagents.
 3. The method of claim 2, wherein in the modular composition, Xof Formula (I), (II) or (III) is —O—, —S— or —CH₂—; and n is 1, 2 or 3.4. The method of claim 2, wherein the modular composition comprises 1-4tetraGalNAc ligands, which may be the same or different.
 5. The methodof claim 2, wherein the modular composition comprises 1-8 peptidesindependently selected from SEQ ID No. 1-474, or the D-amino acid,retro-inverso, and cysteine conjugation point variants thereof, whichmay be the same or different.
 6. The method of claim 1, wherein themodular composition comprises: 1) a double stranded siRNA; 2) 1-8tetraGalNAc ligands of Formula (IV), (V) or (VI):

optionally, 3) 1-16 linkers, which may be the same or different;optionally, 4) 1-8 peptides independently selected from SEQ ID No.1-474, or the D-amino acid, retro-inverso, and cysteine conjugationpoint variants thereof, which may be the same or different; andoptionally, 5) 1-8 targeting ligands, solubilizing agents,pharmacokinetics enhancing agents, lipids, and/or masking agents.
 7. Themethod of claim 6, wherein the tetraGalNAc ligands and/or the peptides,if present, are attached to the siRNA at different 2′-positions of theribose rings and/or at different terminal 3′ and/or 5′-positions of thesiRNA; and wherein the tetraGalNAc ligands and/or the peptides, ifpresent, are attached to the siRNA optionally via linkers.
 8. The methodof claim 6, wherein the modular composition comprises 1-8 peptidesindependently selected from SEQ ID No. 1-474, or the D-amino acid,retro-inverso, and cysteine conjugation point variants thereof, whichmay be the same or different.
 9. The method of claim 8, wherein themodular composition comprises 1-8 peptides independently selected fromSEQ ID No. 2, 3, 5, 7, 11, 13, 19, 22, 27-32, 55, 56, 63, 64, 69, 71-74,86, 90, 94, 95, 106, 137, 192, 200, 201, 228, 229, 266, 282, 333, 337,407, 423, 436, 437, 461-463, 467, 468, 470, 473 and 474, or the D-aminoacid, retro-inverso, and cysteine conjugation point variants thereof,which may be the same or different.
 10. The method of claim 1, whereinthe subject in need is human, and the method is carried out in vitro, exvivo, or in vivo.
 11. A method for inhibiting the expression of a targetgene in a cell of a subject in need, comprising: contacting the cellwith a modular composition, comprising: 1) a single stranded or doublestranded oligonucleotide; 2) one or more tetraGalNAc ligands of Formula(I), (II) or (III), which may be the same or different:

wherein: X is —O—, —S—, —CR¹R²— or —NR¹—; R¹ and R² are eachindependently selected from the group consisting of hydrogen and C₁-C₆alkyl; n is 1, 2, 3, or 4; and the bond with “

” indicates the point of attachment of the tetraGalNAc ligands to theoligonucleotide; optionally, 3) one or more linkers, which may be thesame or different; optionally, 4) one or more peptides independentlyselected from SEQ ID No. 1-474, or the D-amino acid, retro-inverso, andcysteine conjugation point variants thereof, which may be the same ordifferent, wherein the cysteine conjugation point variants thereofrefers to variants of the peptides comprising a cysteine conjugation, ora cysteine or other thiol-containing moiety added to the C- orN-terminus of the peptides; and optionally, 5) one or more targetingligands, solubilizing agents, pharmacokinetics enhancing agents, lipids,and/or masking agents, wherein the oligonucleotide is present in anamount sufficient to inhibit expression of the target gene.
 12. Themethod of claim 11, wherein the modular composition comprises: 1) asingle stranded or double stranded siRNA; 2) 1-8 tetraGalNAc ligands ofFormula (I), (II) or (III), which may be the same or different; 3) 1-24linkers, which may be the same or different; optionally, 4) 1-8 peptidesindependently selected from SEQ ID No. 1-474, or the D-amino acid,retro-inverso, and cysteine conjugation point variants thereof, whichmay be the same or different; and optionally, 5) 1-8 targeting ligands,solubilizing agents, pharmacokinetics enhancing agents, lipids, and/ormasking agents.
 13. The method of claim 12, wherein in the modularcomposition, X of Formula (I), (II) or (III) is —O—, —S— or —CH₂—; and nis 1, 2 or
 3. 14. The method of claim 12, wherein the modularcomposition comprises 1-4 tetraGalNAc ligands, which may be the same ordifferent.
 15. The method of claim 12, wherein the modular compositioncomprises 1-8 peptides independently selected from SEQ ID No. 1-474, orthe D-amino acid, retro-inverso, and cysteine conjugation point variantsthereof, which may be the same or different.
 16. The method of claim 11,wherein the modular composition comprises: 1) a double stranded siRNA;2) 1-8 tetraGalNAc ligands of Formula (IV), (V) or (VI):

optionally, 3) 1-16 linkers, which may be the same or different;optionally, 4) 1-8 peptides independently selected from SEQ ID No.1-474, or the D-amino acid, retro-inverso, and cysteine conjugationpoint variants thereof, which may be the same or different; andoptionally, 5) 1-8 targeting ligands, solubilizing agents,pharmacokinetics enhancing agents, lipids, and/or masking agents. 17.The method of claim 16, wherein the tetraGalNAc ligands and/or thepeptides, if present, are attached to the siRNA at different2′-positions of the ribose rings and/or at different terminal 3′ and/or5′-positions of the siRNA; and wherein the tetraGalNAc ligands and/orthe peptides, if present, are attached to the siRNA optionally vialinkers.
 18. The method of claim 16, wherein the modular compositioncomprises 1-8 peptides independently selected from SEQ ID No. 1-474, orthe D-amino acid, retro-inverso, and cysteine conjugation point variantsthereof, which may be the same or different.
 19. The method of claim 18,wherein the modular composition comprises 1-8 peptides independentlyselected from SEQ ID No. 2, 3, 5, 7, 11, 13, 19, 22, 27-32, 55, 56, 63,64, 69, 71-74, 86, 90, 94, 95, 106, 137, 192, 200, 201, 228, 229, 266,282, 333, 337, 407, 423, 436, 437, 461-463, 467, 468, 470, 473 and 474,or the D-amino acid, retro-inverso, and cysteine conjugation pointvariants thereof, which may be the same or different.
 20. The method ofclaim 11, wherein the subject in need is human, and the method iscarried out in vitro, ex vivo, or in vivo.